CN114206860A - Bicyclic derivatives for the treatment of endoparasites - Google Patents

Bicyclic derivatives for the treatment of endoparasites Download PDF

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Publication number
CN114206860A
CN114206860A CN202080055095.0A CN202080055095A CN114206860A CN 114206860 A CN114206860 A CN 114206860A CN 202080055095 A CN202080055095 A CN 202080055095A CN 114206860 A CN114206860 A CN 114206860A
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alkyl
dihydro
carboxamide
benzoxazin
quinoline
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P·杜克雷
F·保特拉
D·拉若
C·塔赫陶伊
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Lilan Animal Health Care Co ltd
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Lilan Animal Health Care Co ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/10—Anthelmintics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
    • C07D265/34—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings
    • C07D265/36—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings condensed with one six-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

The present invention provides compounds of formula (I):

Description

Bicyclic derivatives for the treatment of endoparasites
Cross Reference to Related Applications
This application claims priority to U.S. provisional application 62/858,465 filed on 7.6.2019 and U.S. provisional application 62/947,852 filed on 13.12.2019, the contents of each of which are incorporated herein by reference in their entirety.
Technical Field
The present invention relates to medical chemistry, pharmacology, and veterinary and human medicine. More particularly, the present invention relates to compounds of formula (I) and their use in the control of endoparasites, such as heartworm, in warm-blooded animals.
Background
Heartworm (heartworm) is a parasitic roundworm that is transmitted between hosts by mosquito bites. The life cycle begins when the female mosquito obtains blood feed from the infected host. Mosquitoes ingest immature heartworms, which then molt to an infectious larval stage and travel to the mouth of the mosquito. The mosquitoes then feed on a susceptible host, such as a dog or cat, and thereby inject infected larvae. The larvae then molt in the new host to the next larval stage and then migrate in vivo, eventually entering the blood vessels. As the larvae migrate within the tissue, they molt adult lightness adults. Young adults eventually migrate into the pulmonary vessels where they mature into sexually active adults. Adult heartworms then multiply and release immature heartworms, completing the cycle. Heartworm infection may cause serious disease to the host.
Adult heartworm infections may be treated with arsenic-based compounds; such treatments are time consuming, cumbersome and often only partially successful. Therefore, the focus of treatment is to control heartworm infection. Heartworm control is currently only performed by regular administration throughout the year. Typical treatments include macrolides such as ivermectin (ivermectin), moxidectin (moxidectin) and milbemycin oxime (milbemycin oxime). Unfortunately, resistance to macrolides has been observed by heartworm (Dirofilaria immitis). Thus, there is a need for new compounds that effectively control heartworm infection by preventing or by directly killing heartworms. Certain treatments for endoparasites are described in WO 2017/178416, WO 2018/087036, WO 2018/197401, WO 2019/025341 and WO 2019/002132.
Disclosure of Invention
The present invention provides compounds of formula (I) that are effective in the treatment and/or control of endoparasites (e.g., heartworm) in a warm-blooded animal.
In one embodiment, the present invention provides a compound of formula (I):
Figure BDA0003493730300000021
wherein
n is 0 or 1;
X1selected from N and CR1；
X2Selected from N and CR2；
X3Selected from N and CR3；
X4Selected from N and CR4；
X5Selected from N and CR5；
X6Selected from N and CR6；
G is selected from
Figure BDA0003493730300000022
M is selected from N-R13O and S;
Y1selected from the group consisting of CR8R9O, S and NR10；
Y2Selected from the group consisting of CR8R9O, S and NR10；
Wherein the radical Y1Or Y2At least one of which is CR8R9；
Z1Selected from N, O, S and CR11；
Z2Selected from the group consisting of none, N and CR11；
Z3Selected from the group consisting of none, N and CR11；
Z4Selected from N, O, S and CR11；
Wherein Z1、Z2、Z3And Z4Is not more than 2 of N and wherein Z is1And Z4Only one of them is O or S, only when Z is1Z when O or S is2Is absent, and only if Z4Z when O or S is3Is absent;
R1selected from: hydrogen; halogen; a hydroxyl group; -SH; -SC1-C4An alkyl group; (C) S (O)1-C4Alkyl groups); -S (O)2(C1-C4Alkyl groups); a cyano group; c1-C4An alkyl group; c1-C4A haloalkyl group; c1-C4-an alkoxy group; -B (OR)15)(OR16) Wherein R is15Selected from hydrogen, C at each application1-C4Alkyl and C3-C6Cycloalkyl radical, R16Selected from hydrogen, C at each application1-C4Alkyl and C3-C6Cycloalkyl, or R15And R16Together with the oxygen atom to which they are attached form a 5-to 7-membered ring, optionally substituted by 1 to 4C1-C4Alkyl substituted; -NH2；-NH(C1-C4Alkyl groups); and-N (C)1-C4Alkyl radical)2；
R2Selected from: hydrogen; halogen; a hydroxyl group; -SH; -SC1-C4An alkyl group; (C) S (O)1-C4Alkyl groups); -S (O)2(C1-C4Alkyl groups); a cyano group; c1-C4An alkyl group; c1-C4A haloalkyl group; c1-C4-an alkoxy group; -B (OR)15)(OR16) Wherein R is15Selected from hydrogen, C at each application1-C4Alkyl and C3-C6Cycloalkyl radical, R16Selected from hydrogen, C at each application1-C4Alkyl and C3-C6Cycloalkyl, or R15And R16Together with the oxygen atom to which they are attached form a 5-to 7-membered ring, optionally substituted by 1 to 4C1-C4Alkyl substituted; -NH2；-NH(C1-C4Alkyl groups); and-N (C)1-C4Alkyl radical)2；
R3Selected from: hydrogen; halogen; a hydroxyl group; -SH; -SC1-C4An alkyl group; (C) S (O)1-C4Alkyl groups); -S (O)2(C1-C4Alkyl groups); a cyano group; c1-C4An alkyl group; c1-C4A haloalkyl group; c1-C4-an alkoxy group; -B (OR)15)(OR16) Wherein R is15Selected from hydrogen, C at each application1-C4Alkyl and C3-C6Cycloalkyl radical, R16Selected from hydrogen, C at each application1-C4Alkyl and C3-C6Cycloalkyl, or R15And R16Together with the oxygen atom to which they are attached form a 5-to 7-membered ring, optionally substituted by 1 to 4C1-C4Alkyl substituted; -NH2；-NH(C1-C4Alkyl groups); and-N (C)1-C4Alkyl radical)2；
R4Selected from: halogen; a cyano group; -CHO; a hydroxyl group; c1-C4An alkyl group; c2-C4An alkenyl group; c2-C4An alkynyl group; c3-C6A cycloalkyl group; c1-C4A haloalkyl group; c1-C4-alkoxy-substituted-C1-C4An alkyl group; benzyl optionally substituted with 1 to 5 halogen atoms; c1-C4An alkoxy group; -NH2；-NH(C1-C4Alkyl groups); -N (C)1-C4Alkyl radical)2；
-NH(C3-C6Cycloalkyl groups); -N (C)1-C4Alkyl) (C3-C6-cycloalkyl); -N (C)1-C4Alkyl) (4-to 7-membered heterocycloalkyl); -NH (4-to 7-membered heterocycloalkyl); -N (C)1-C4Alkyl) (C1-C4Alkoxy groups); -C (O) NH (C)1-C4Alkyl groups); -C (O) N (C)1-C4Alkyl radical)2；-C(O)N(C1-C4Alkyl) (4-to 7-membered heterocycloalkyl);
-NHSO2(C1-C4alkyl groups); -SC1-C4An alkyl group; (O) C1-C4An alkyl group; -SO2C1-C4An alkyl group;
-B(OR15)(OR16) Wherein R is15Selected from hydrogen, C at each application1-C4Alkyl and C3-C6Cycloalkyl radical, R16Selected from hydrogen, C at each application1-C4Alkyl and C3-C6Cycloalkyl, or R15And R16Together with the oxygen atom to which they are attached form a 5-to 7-membered ring, optionally substituted by 1 to 4C1-C4Alkyl substituted; 6-or 10-membered aryl; a monocyclic heterocycle selected from the group consisting of 4-to 7-membered heterocycloalkyl, a 5-membered heteroaryl having at least one nitrogen atom through which the 5-membered heteroaryl ring is connected to the remainder of the molecule, and a 6-membered heteroaryl having at least one nitrogen atom; r4Wherein each of the aryl, heterocycloalkyl and heteroaryl rings is optionally substituted with 1,2 or 3 substituents independently selected from halogen, cyano, nitro, hydroxy, oxo, C1-C4Alkyl radical, C3-C6Cycloalkyl radical, C1-C4Haloalkyl, C1-C4Alkoxy, -NH2、-NH(C1-C4Alkyl), -N (C)1-C4Alkyl radical)2、-NH(C3-C6Cycloalkyl), -N (C)1-C4Alkyl) (C3-C6-cycloalkyl), -NHSO2(C1-C4Alkyl), -SC1-C4Alkyl, -S (O) C1-C4Alkyl, -SO2C1-C4Alkyl, -S (O) C1-C4-haloalkyl and-SO2C1-C4Substituted with a substituent of haloalkyl; wherein R is4C in (1)3-C6The cycloalkyl and heterocycloalkyl rings are optionally substituted with a spirocyclic group, wherein said spirocyclic group is a 3-to 6-membered cycloalkyl or a 4-to 6-membered heterocycloalkyl containing 1,2 or 3 heteroatoms independently selected from N, S or O, wherein said spirocyclic group is optionally substituted with 1,2 or 3 heteroatoms independently selected from halogen, cyano, nitro, hydroxy, oxo, C1-C4Alkyl radical, C3-C6Cycloalkyl radical, C1-C4Haloalkyl, C1-C4Alkoxy, -NH2、-NH(C1-C4Alkyl), -N (C)1-C4Alkyl radical)2、-NH(C3-C6Cycloalkyl), -N (C)1-C4Alkyl) (C3-C6-cycloalkyl), -NHSO2(C1-C4Alkyl), -SC1-C4Alkyl, -S (O) C1-C4Alkyl, -SO2C1-C4Alkyl, -S (O) C1-C4-haloalkyl and-SO2C1-C4Substituted with a substituent of haloalkyl; and wherein R4Each of C1-C4Alkyl radical, C3-C6Cycloalkyl and C1-C4Alkoxy can be optionally selected from 1,2 or 3 independently selected from halogen, hydroxy, -NH2、-NH(C1-C4Alkyl), -N (C)1-C4Alkyl radical)2Cyano, carboxy, carbamoyl, C1-C4Alkoxycarbonyl, -C (O) NH (C)1-C4Alkyl), -C (O) N (C)1-C4Alkyl radical)2And C1-C4Substituted by a substituent of alkoxy;
R5selected from: hydrogen; halogen; a hydroxyl group; -SH; -SC1-C4An alkyl group; (C) S (O)1-C4Alkyl groups); -S (O)2(C1-C4Alkyl groups); a cyano group; c1-C4An alkyl group; c1-C4A haloalkyl group; c1-C4-an alkoxy group; -B (OR)15)(OR16) Wherein R is15Selected from hydrogen, C at each application1-C4Alkyl and C3-C6Cycloalkyl radical, R16Selected from hydrogen, C at each application1-C4Alkyl and C3-C6Cycloalkyl, or R15And R16Together with the oxygen atom to which they are attached form a 5-to 7-membered ring, optionally substituted by 1 to 4C1-C4Alkyl substituted; -NH2；-NH(C1-C4Alkyl groups); and-N (C)1-C4Alkyl radical)2；
R6Selected from: hydrogen; halogen; a hydroxyl group; -SH; -SC1-C4An alkyl group; (C) S (O)1-C4Alkyl groups); -S (O)2(C1-C4Alkyl groups); a cyano group; c1-C4An alkyl group; c1-C4A haloalkyl group; c1-C4-an alkoxy group; -B (OR)15)(OR16) Wherein R is15Selected from hydrogen, C at each application1-C4Alkyl and C3-C6Cycloalkyl radical, R16Selected from hydrogen, C at each application1-C4Alkyl and C3-C6Cycloalkyl, or R15And R16Together with the oxygen atom to which they are attached form a 5-to 7-membered ring, optionally substituted by 1 to 4C1-C4Alkyl substituted; -NH2；-NH(C1-C4Alkyl groups); and-N (C)1-C4Alkyl radical)2；
R7Selected from: hydrogen; c1-C4An alkyl group; and C optionally substituted by 1 to 5 halogen atoms3-C6A cycloalkyl group; -C (H) O; c2-C4An alkenyl group; c2-C4An alkynyl group; c1-C4A haloalkyl group; and C1-C4-alkoxy radical；
R8Independently at each selection from hydrogen, fluorine and C1-C4An alkyl group;
R9independently at each selection from hydrogen, fluorine and C1-C4An alkyl group;
R10selected from hydrogen and C1-C4An alkyl group;
R11independently at each selection from hydrogen, halogen, hydroxy, cyano, C1-C4Alkyl radical, C1-C4Haloalkyl, C1-C4-alkoxy, C3-C6Cycloalkyl, -NH2、-NH(C1-C4Alkyl) and-N (C)1-C4Alkyl radical)2(ii) a And Q is selected from
(i) 6-or 10-membered aryl, optionally substituted with 1,2,3, 4 or 5 independently selected from halogen, cyano, nitro, hydroxy, C1-C4Alkyl radical, C1-C4Haloalkyl, C1-C4Alkoxy radical, C3-C6Cycloalkyl, -NH2、-NH(C1-C4Alkyl), -N (C)1-C4Alkyl radical)2、-NH(C3-C6Cycloalkyl), -N (C)1-C4Alkyl) (C3-C6-cycloalkyl), -NHSO2(C1-C4Alkyl), -SC1-C4Alkyl, -S (O) C1-C4Alkyl, -SO2C1-C4Alkyl, -S (O) C1-C4-haloalkyl and-SO2C1-C4Haloalkyl, wherein said 6-or 10-membered aryl is optionally fused with a 4-to 7-membered heterocycloalkyl having 1 or 2 heteroatoms selected from O, S and N, and wherein the carbon of the heterocycloalkyl is optionally substituted with 1,2 or 3 substituents independently selected from halogen, cyano, nitro, hydroxy, oxo, C1-C4Alkyl radical, C3-C6Cycloalkyl radical, C1-C4Haloalkyl, C1-C4Alkoxy, -NH2、-NH(C1-C4Alkyl) and-N (C)1-C4Alkyl radical)2And any N in the heterocycloalkyl group is selected from hydrogen, C, where the valence allows1-C4Alkyl and C3-C6Cycloalkyl, substituted with a substituent;
(ii) 5-to 10-membered heteroaryl having 1,2, or 3 heteroatoms independently selected from O, S and N, wherein the carbons of the 5-to 10-membered heteroaryl are optionally substituted with 1,2,3, 4, or 5 heteroatoms independently selected from halogen, cyano, nitro, hydroxy, C1-C4Alkyl radical, C3-C6Cycloalkyl radical, C1-C4Haloalkyl, C1-C4Alkoxy, benzyloxy, -NH2、-NH(C1-C4Alkyl), -N (C)1-C4Alkyl radical)2、-SC1-C4Alkyl, -S (O) C1-C4Alkyl, -SO2C1-C4Alkyl, -S (O) C1-C4-haloalkyl and-SO2C1-C4Haloalkyl, and any N in the heteroaryl is optionally substituted, as permitted by the valence, with a substituent selected from hydrogen, C1-C4Alkyl and C3-C6Cycloalkyl, substituted with a substituent;
(iii) 4-to 7-membered heterocycloalkyl having 1,2 or 3 heteroatoms independently selected from O, S and N, wherein said heterocycloalkyl is optionally benzo-fused, wherein the carbons of said 4-to 7-membered heterocycloalkyl or optionally benzo-fused 4-to 7-membered heterocycloalkyl are optionally substituted with 1,2,3 or 4 heteroatoms independently selected from halogen, cyano, nitro, hydroxy, oxo, C1-C4Alkyl radical, C3-C6Cycloalkyl radical, C1-C4Haloalkyl, C1-C4Alkoxy, -NH2、-NH(C1-C4Alkyl) and-N (C)1-C4Alkyl radical)2And any N in the heterocycloalkyl is optionally selected from hydrogen, C1-C4Alkyl and C3-C6Cycloalkyl, substituted with a substituent;
(iv) 6-or 10-membered aryloxy optionally substituted with 1,2 or 3 substituents independently selected from halogen, cyano, nitro, hydroxyBase, C1-C4Alkyl radical, C3-C6Cycloalkyl radical, C1-C4Haloalkyl, C1-C4Alkoxy, -NH2、-NH(C1-C4Alkyl group), N (C)1-C4Alkyl radical)2、-NH(C3-C6Cycloalkyl), -N (C)1-C4Alkyl) (C3-C6-cycloalkyl), -NHSO2(C1-C4Alkyl), -SC1-C4Alkyl, -S (O) C1-C4Alkyl, -SO2C1-C4Alkyl, -S (O) C1-C4-haloalkyl and-SO2C1-C4Substituted with a substituent of haloalkyl;
(v) 6-or 10-membered arylthioxy, optionally substituted by 1,2 or 3 substituents independently selected from halogen, cyano, nitro, hydroxy, C1-C4Alkyl radical, C3-C6Cycloalkyl radical, C1-C4Haloalkyl, C1-C4Alkoxy, -NH2、-NH(C1-C4Alkyl group), N (C)1-C4Alkyl radical)2、-NH(C3-C6Cycloalkyl), -N (C)1-C4Alkyl) (C3-C6-cycloalkyl), -NHSO2(C1-C4Alkyl), -SC1-C4Alkyl, -S (O) C1-C4Alkyl, -SO2C1-C4Alkyl, -S (O) C1-C4-haloalkyl and-SO2C1-C4Substituted with a substituent of haloalkyl; and
(vi) 5-to 10-membered heteroaryloxy, optionally substituted with 1,2 or 3 substituents independently selected from halogen, cyano, nitro, hydroxy, oxo, C1-C4Alkyl radical, C3-C6Cycloalkyl radical, C1-C4Haloalkyl, C1-C4Alkoxy, -NH2、-NH(C1-C4Alkyl group), N (C)1-C4Alkyl radical)2、-NH(C3-C6Cycloalkyl), -N (C)1-C4Alkyl) (C3-C6-cycloalkyl), -NHSO2(C1-C4Alkyl), -SC1-C4Alkyl, -S (O) C1-C4Alkyl, -SO2C1-C4Alkyl, -S (O) C1-C4-haloalkyl and-SO2C1-C4Substituted with a substituent of haloalkyl;
R13selected from hydroxy, C1-C4Alkoxy and-NH2(ii) a And
R14independently selected at each selection from hydrogen, halogen, cyano, nitro, hydroxy, C1-C4Alkyl radical, C3-C6Cycloalkyl radical, C1-C4Haloalkyl, C1-C4Alkoxy radical, C1-C4Haloalkoxy, -NH2、-NH(C1-C4Alkyl) and-N (C)1-C4Alkyl radical)2；
Or a salt thereof.
In one embodiment, the present invention also provides a composition comprising: a compound of formula (I) or a salt thereof and an acceptable excipient, said composition optionally further comprising at least one additional active compound.
In one embodiment, the present invention also provides a method of treating a parasite comprising: administering to a subject in need thereof an effective amount of a compound of formula (I) or a salt thereof, optionally further comprising an effective amount of at least one additional active compound.
In one embodiment, the present invention also provides a method of controlling parasites, comprising: administering to a subject in need thereof an effective amount of a compound of formula (I) or a salt thereof, optionally further comprising an effective amount of at least one additional active compound.
In one embodiment, the invention also provides a method of treating or controlling a parasite comprising: contacting the environment of a subject with an effective amount of a compound of formula (I) or a salt thereof, said method optionally further comprising an effective amount of at least one additional active compound.
Accordingly, the present invention provides the use of a compound of the invention as a medicament, including for the manufacture of a medicament. In one embodiment, the present invention provides the manufacture of a medicament comprising a compound of formula (I) or a salt thereof for use in the treatment of parasites. In one embodiment, the present invention provides the manufacture of a medicament comprising a compound of formula (I) or a salt thereof for controlling parasites.
The invention also provides processes for preparing the compounds of the invention and intermediates thereof.
Detailed Description
The term "C1-C4Alkyl "refers to a straight or branched alkyl chain having from one to four carbon atoms and includes methyl, ethyl, propyl, isopropyl, butyl, and the like.
The term "C1-C4Haloalkyl "means a straight or branched alkyl chain having one to four carbon atoms and 1 to 5 halogens and includes fluoromethyl, difluoromethyl, trifluoromethyl, 2,2, 2-trifluoroethyl, 1,2, 2-trifluoroethyl, 3,3, 3-trifluoropropyl, and the like.
The term "C2-C4Alkenyl "refers to a straight or branched alkenyl chain having two to four carbon atoms and one carbon-carbon double bond, and includes ethylene, propylene, isopropylene, butylene, isobutylene, sec-butylene, and the like.
The term "C2-C4Alkynyl "refers to straight or branched alkynyl chains having two to four carbon atoms and one carbon-carbon triple bond and includes acetylene, propargyl, and the like.
The term "C1-C4Alkoxy "means C attached through an oxygen atom1-C4Alkyl and includes methoxy, ethoxy, propoxy, isopropoxy, butoxy and the like.
The term "C3-C6Cycloalkyl "refers to an alkyl ring of three to six carbon atoms and includes cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
The terms "halogen" and "halo" refer to a chlorine, fluorine, bromine or iodine atom.
The term "C6-or C10-membered aryl "means phenyl or naphthyl.
The term "C6-or C10-aryloxy "means a phenyl or naphthyl group linked through an oxygen atom and includes phenoxy and naphthoxy groups.
The term "C6-or C10The "arylthio-oxy" refers to a phenyl group or a naphthyl group linked through a sulfur atom, and includes phenylthio and naphthylthio. It is also understood that the term "C6-or C10The radical-arylthioxy "also covers compounds in which sulfur is-SO2and-S (O) -.
The term "4-to 7-membered heterocycloalkyl" refers to a 4-to 7-membered monocyclic saturated or partially (but not fully) unsaturated ring having one or more heteroatoms, preferably one, two or three heteroatoms, selected from nitrogen, oxygen and sulfur, and which optionally includes a carbonyl group to form a lactam or lactone. It will be understood that where sulfur is included, the sulfur may be-S-, -SO-or-SO2-. Such terms include, by way of example and not limitation, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, oxetanyl, dioxolanyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrofuranyl, hexahydropyrimidyl, tetrahydropyrimidinyl, dihydroimidazolyl, and the like.
The term "5-membered heteroaryl" refers to a five-membered monocyclic fully unsaturated ring having one to four carbon atoms and one to four heteroatoms selected from nitrogen, oxygen, and sulfur. Such terms include, for example and without limitation, furyl, thienyl, pyrrolyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, and the like. It is understood that a 5-membered heteroaryl group can be attached as a substituent through a ring carbon or ring nitrogen atom, where such modes of attachment are available, e.g., for pyrrolyl, imidazolyl, pyrazolyl, triazolyl, and the like.
The term "6-membered heteroaryl" refers to a six-membered monocyclic fully unsaturated ring having one to five carbon atoms and one or more, typically one to four heteroatoms selected from nitrogen, oxygen and sulfur. Such terms include, for example and without limitation, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, and the like. It is understood that a 6-membered heteroaryl group may be attached as a substituent through a ring carbon or ring nitrogen atom, where such a mode of attachment is available.
The term "5-to 10-membered heteroaryl" refers to a five-to ten-membered monocyclic or polycyclic fully unsaturated ring or ring system having one to nine carbon atoms and one or more heteroatoms, preferably one, two or three heteroatoms, selected from nitrogen, oxygen and sulfur. Such terms include, for example and without limitation, furyl, thienyl, pyrrolyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, thiazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, aza-as
Figure BDA0003493730300000081
Radical diaza
Figure BDA0003493730300000082
A phenyl group, a benzofuranyl group, a benzothiophenyl group, an indolyl group, an isoindolyl group, a benzimidazolyl group, a benzisothiazolyl group, a benzisoxazolyl group, a benzoxazolyl group, a benzopyrazinyl group, a benzopyrazolyl group, a quinazolinyl group, a thienopyridyl group, a quinolyl group, an isoquinolyl group, a benzothiazolyl group, and the like. It is understood that 5-to 10-membered heteroaryl groups having 1,2 or 3 heteroatoms selected from O, S and N may be attached as substituents through ring carbon or ring nitrogen atoms, where such modes of attachment are available.
The term "5-to 10-membered heteroaryloxy" refers to a 5-to 10-membered heteroaryl group having one or more heteroatoms selected from O, S and N, preferably 1,2 or 3 heteroatoms selected from O, S and N, attached through an oxygen atom, and includes imidazolyloxy, pyrazolyloxy, pyridyloxy, pyrimidyloxy, quinolinyloxy and the like.
The term "oxo" refers to a carbonyl group in which an oxygen atom is double bonded to the carbon to which it is attached to form a ketone or aldehyde. For example, a pyridone radical is considered to be an oxo-substituted 6-membered heteroaryl.
The term "carboxy" refers to the following groups:
Figure BDA0003493730300000091
the term "carbamoyl" refers to the following group:
Figure BDA0003493730300000092
the term "C1-C4Alkoxycarbonyl "refers to the following groups:
Figure BDA0003493730300000093
wherein R is C1-C4An alkyl group.
The term "free" as used herein with respect to a group, substituent, moiety, etc., means that the group, substituent or moiety is not present. If a group, substituent or moiety is generally bonded to two or more other groups, substituents or moieties, the other groups, substituents or moieties are bonded together and replaced with an absent group, substituent or moiety. For example, for a compound having the structure A-B-C; wherein B is absent, A is directly bonded to C and the compound is A-C. As another example, for a compound having the structure a-B-C; wherein C is nothing, then the compound is A-B.
The term "salt" refers to a salt of a veterinary or pharmaceutically acceptable organic or inorganic acid and base. Such salts are well known in the art and include those described in Journal of Pharmaceutical Science,66,2-19 (1977). One example is the hydrochloride salt.
The term "substituted," including when used in "optionally substituted," means that one or more hydrogen radicals of a group are replaced with a non-hydrogen radical (substituent). It is understood that at each substitution position, the substituent may be the same or different. Combinations of groups and substituents contemplated by the present invention are those that are stable or chemically feasible. For the compounds described herein, the groups and substituents may be selected according to the allowed valences of the atoms and substituents, such that the selection and substitution results in a stable compound, e.g., that does not spontaneously undergo transformation, such as by rearrangement, cyclization, elimination, and the like.
It is to be understood that when a cycloalkyl or heterocycloalkyl ring is substituted with a spiro group, the spiro group may be attached, where valence permits, to any position of the cycloalkyl or heterocycloalkyl ring, thereby forming an additional ring such that the spiro group is attached to the cycloalkyl or heterocycloalkyl ring through a common atom. Examples of such spiro-substituted rings include 2-oxa-6-azaspiro [3.3] heptane, 2-azaspiro [3.4] octane, 6-oxa-2-azaspiro [3.4] octane and the like.
The term "stable" refers to a compound that does not substantially change when subjected to conditions that allow its generation. In one non-limiting example, a stable compound or chemically feasible compound is one that does not substantially change when held at a temperature of 40 ℃ or less for about one week in the absence of moisture or other chemically reactive conditions.
It is to be understood that where the terms defined herein refer to the number of carbon atoms, the numbers referred to refer to the groups referred to, and do not include any carbon that may be present in any optional substituent thereon or that may be present as part of a fused ring, including benzo fused rings.
Those skilled in the art will appreciate that certain compounds of the present invention exist as isomers. All stereoisomers of the compounds of the present invention, including geometric isomers, enantiomers and diastereomers in any ratio, are contemplated as being within the scope of the present invention.
Those skilled in the art will also appreciate that certain compounds of the present invention exist as tautomers. All tautomeric forms of the compounds of the invention are considered to be within the scope of the invention.
The compounds of the present invention also include all isotopic variations, in which at least one atom having a predominant atomic mass is replaced by an atom having the same atomic number but an atomic mass different from the predominant atomic mass. Isotopic variations (e.g., deuterium,2H) May provide greater metabolic stabilityAnd (5) performing qualitative determination. In addition, certain isotopic variations of the compounds of the present invention can incorporate a radioactive isotope (e.g., tritium)3H or14C) Which may be useful in drug and/or substrate tissue distribution studies. With positron-emitting isotopes such as11C、18F、15O and13n substitution may be useful in Positron Emission Tomography (PET) studies.
The term "a compound of the present invention (a compound of the invention/a compound of the invention, etc.) includes embodiments of formula (I) and other more particular embodiments encompassed by formula (I) described herein and exemplary compounds described herein and salts of each of these embodiments.
Compounds of formula (I) having G as defined have the formula:
Figure BDA0003493730300000111
further embodiments of the compounds of the present invention are provided below:
(a) one embodiment relates to compounds of formula (Ia).
(b) One embodiment relates to compounds of formula (Ib).
(1) One embodiment relates to compounds of formula (Ic).
(2) One embodiment relates to compounds of formula (I), embodiment (a), embodiment (b) and (1), wherein X1、X2、X3And X5Is N.
(c) One embodiment relates to compounds of formula (I), formula (Ia), formula (Ib) or formula (Ic), wherein X1Is CR1；X2Is CR2；X3Is CR3；X4Is CR4；X5Is CR5(ii) a And X6Is N; or a salt thereof.
(d) One embodiment relates to compounds of formula (I), formula (Ia), formula (Ib) or formula (Ic), wherein X1Is CR1；X2Is CR2；X3Is CR3；X4Is CR4；X5Is N; and X6Is N; or a salt thereof.
(e) One embodiment relates to compounds of formula (I), formula (Ia) or formula (Ib)), wherein X1Is CR1；X2Is CR2；X3Is CR3；X4Is CR4；X5Is N; and X6Is CR6(ii) a Or a salt thereof.
(f) One embodiment relates to compounds of formula (I), formula (Ia), formula (Ib) or formula (Ic), wherein X1Is CR1；X2Is CR2；X3Is CR3；X4Is N; x5Is N; and X6Is N; or a salt thereof.
(g) One embodiment relates to compounds of formula (I) and embodiments (a), (b), (1), (2), (C), (d), (e) and (f) wherein Q is 6-or 10-membered aryl, optionally substituted with 1,2 or 3 substituents independently selected from halogen, cyano, nitro, hydroxy, C1-C4Alkyl radical, C1-C4Haloalkyl, C1-C4Alkoxy radical, C3-C6Cycloalkyl, -NH2、-NH(C1-C4Alkyl), -N (C)1-C4Alkyl radical)2、-NH(C3-C6Cycloalkyl), -N (C)1-C4Alkyl) (C3-C6-cycloalkyl), -NHSO2(C1-C4Alkyl), -SC1-C4Alkyl, -S (O) C1-C4Alkyl, -SO2C1-C4Alkyl, -S (O) C1-C4-haloalkyl and-SO2C1-C4Substituted with a substituent of haloalkyl; or a salt thereof.
(h) One embodiment relates to compounds of formula (I) and embodiments (a), (b), (1), (2), (C), (d), (e) and (f) wherein Q is a 6-membered aryl group, optionally substituted with 1,2 or 3 substituents independently selected from halogen, cyano, nitro, hydroxy, C1-C4Alkyl radical, C1-C4Haloalkyl, C1-C4Alkoxy radical, C3-C6Cycloalkyl, -NH2、-NH(C1-C4Alkyl), -N (C)1-C4Alkyl radical)2、-NH(C3-C6Cycloalkyl), -N (C)1-C4Alkyl) (C3-C6-cycloalkyl), -NHSO2(C1-C4Alkyl), -SC1-C4Alkyl, -S (O) C1-C4Alkyl, -SO2C1-C4Alkyl, -S (O) C1-C4-haloalkyl and-SO2C1-C4Haloalkyl, wherein said 6-membered aryl is fused with a 4-to 7-membered heterocycloalkyl having 1 or 2 heteroatoms selected from O, S and N and wherein the carbon of said heterocycloalkyl is optionally substituted with 1,2 or 3 substituents independently selected from halogen, cyano, nitro, hydroxy, oxo, C1-C4Alkyl radical, C3-C6Cycloalkyl radical, C1-C4Haloalkyl, C1-C4Alkoxy, -NH2、-NH(C1-C4Alkyl) and-N (C)1-C4Alkyl radical)2And any N in the heterocycloalkyl is selected from hydrogen, C1-C4Alkyl and C3-C6Cycloalkyl, substituted with a substituent; or a salt thereof.
(i) One embodiment relates to compounds of formula (I) and embodiments (a), (b), (1), (2), (C), (d), (e) and (f) wherein Q is a 5-to 10-membered heteroaryl having 1 or 2 heteroatoms selected from O, S and N and wherein the carbons of said heteroaryl are optionally substituted with 1,2 or 3 heteroatoms independently selected from halogen, cyano, nitro, -OH, C1-C4Alkyl radical, C3-C6Cycloalkyl radical, C1-C4Haloalkyl, C1-C4Alkoxy, -NH2、-NH(C1-C4Alkyl) and-N (C)1-C4Alkyl radical)2And any N in said heteroaryl is optionally selected from hydrogen, C1-C4Alkyl and C3-C6Cycloalkyl, substituted with a substituent; or a salt thereof.
(j) One embodiment relates to compounds of formula (I) and embodiments (a), (b), (1), (2), (C), (d), (e) and (f) wherein Q is a 4-to 7-membered heterocycloalkyl having 1 or 2 heteroatoms selected from O, S and N, wherein the heterocycloalkyl is optionally benzo-fused, wherein the carbon of the heterocycloalkyl or optionally benzo-fused heterocycloalkyl is optionally substituted with 1,2,3 or 4 heteroatoms independently selected from halogen, cyano, nitro, hydroxy, oxo, C1-C4Alkyl radical, C3-C6Cycloalkyl radical, C1-C4Haloalkyl, C1-C4Alkoxy, -NH2、-NH(C1-C4Alkyl) and-N (C)1-C4Alkyl radical)2And any N in the heterocycloalkyl is optionally selected from hydrogen, C1-C4Alkyl and C3-C6Cycloalkyl, substituted with a substituent; or a salt thereof.
(k) One embodiment relates to compounds of formula (I) and embodiments (a), (b), (1), (2), (C), (d), (e) and (f) wherein Q is 6-or 10-membered aryloxy optionally substituted with 1,2 or 3 independently selected from halogen, cyano, nitro, hydroxy, C1-C4Alkyl radical, C3-C6Cycloalkyl radical, C1-C4Haloalkyl, C1-C4Alkoxy, -NH2、-NH(C1-C4Alkyl), -N (C)1-C4Alkyl radical)2、-NH(C3-C6Cycloalkyl), -N (C)1-C4Alkyl) (C3-C6-cycloalkyl), -NHSO2(C1-C4Alkyl), -SC1-C4Alkyl, -S (O) C1-C4Alkyl, -SO2C1-C4Alkyl, -S (O) C1-C4-haloalkyl and-SO2C1-C4Substituted with a substituent of haloalkyl; or a salt thereof.
(l) One embodiment relates to compounds of the formula (I) and embodiments (1), (2), (a), (b), (c), (d), (e) and (f), wherein Q is a 5-to 10-membered heteroaryloxy group, which is optionally substituted by 12 or 3 are independently selected from halogen, cyano, nitro, hydroxy, oxo, C1-C4Alkyl radical, C3-C6Cycloalkyl radical, C1-C4Haloalkyl, C1-C4Alkoxy, -NH2、-NH(C1-C4Alkyl), -N (C)1-C4Alkyl radical)2、-NH(C3-C6Cycloalkyl), -N (C)1-C4Alkyl) (C3-C6-cycloalkyl), -NHSO2(C1-C4Alkyl), -SC1-C4Alkyl, -S (O) C1-C4Alkyl, -SO2C1-C4Alkyl, -S (O) C1-C4-haloalkyl and-SO2C1-C4Substituted with a substituent of haloalkyl; or a salt thereof.
(m) one embodiment relates to compounds of formula (I) and embodiments (a), (b), (1), (2), (c), (d), (e), (f), (g), (h), (I), (j), (k), and (l), wherein n is 1; or a salt thereof.
(n) one embodiment relates to compounds of formula (I) and embodiments (a), (b), (1), (2), (c), (d), (e) and (f), (g), (h), (I), (j), (k), (l) and (m), wherein Y1Is CR8R9And Y is2Is O; or a salt thereof;
(o) one embodiment relates to compounds of formula (I) and embodiments (a), (b), (1), (2), (c), (d), (e), (f), (g), (h), (I), (j), (k), (l), (m) and (n), wherein R4Is selected from C1-C4Alkyl radical, C3-C6Cycloalkyl, -N (C)1-C4Alkyl radical)2And 4-to 7-membered heterocycloalkyl; or a salt thereof.
(p) one embodiment relates to compounds of formula (I) and embodiments (a), (b), (1), (2), (c), (d), (e), (f), (1), (2), (g), (h), (I), (j), (k), (l), (m) and (n), wherein R4is-N (C)1-C4Alkyl radical)2(ii) a Or a salt thereof.
(q) one embodiment relates to compounds of formula (I) and embodiments (a), (b), (1), (2), (c), (d), (e), (f), (g), (h), (I), (j), (k), (l), (M), (n), (O) and (p) wherein M is O; or a salt thereof.
(r) one embodiment relates to compounds of formula (I) and embodiments (a), (b), (1), (2), (c), (d), (e), (f), (g), (h), (I), (j), (k), (l), (M), (n), (o) and (p), wherein M is NR13(ii) a Or a salt thereof.
(S) one embodiment relates to compounds of formula (I) and embodiments (a), (b), (1), (2), (c), (d), (e), (f), (g), (h), (I), (j), (k), (l), (M), (n), (o) and (p) wherein M is S; or a salt thereof.
(t) one embodiment relates to compounds of formula (I) and embodiments (a), (b), (1), (2), (c), (d), (e), (f), (g), (h), (I), (j), (k), (l), (m), (n), (o), (p), (q), (r) and(s), wherein Z1Is CR11，Z2Is CR11，Z3Is absent, and Z4Is S; or a salt thereof.
(u) another embodiment relates to salts of each of the exemplified compounds.
Another embodiment provides a compound of the formula:
Figure BDA0003493730300000141
Figure BDA0003493730300000151
Figure BDA0003493730300000161
or a salt of any of the foregoing;
wherein X1、X2、X3、X4、X5、X6、R1、R4、R5、R7And Q is as defined in the summary of the invention.
In formulae (Ia-1) to (Ia-8a) [ i.e., formulae(Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), (Ia-6), (Ia-7), (Ia-8), (Ia-1a), (Ia-2a), (Ia-3a), (Ia-4a), (Ia-5a), (Ia-6a), (Ia-7a) and (Ia-8a)]In another embodiment of (1), R1When present [ i.e. when explicitly depicted in a formula]Selected from hydrogen, halogen and cyano. In another embodiment of formulae (Ia-1) to (Ia-8a), R1When present, is selected from hydrogen, fluoro and cyano. In another embodiment of formulae (Ia-1) to (Ia-8a), R1When present, is hydrogen or fluorine. In another embodiment of formulae (Ia-1) to (Ia-8a), R1When present, is hydrogen. In another embodiment of formulae (Ia-1) to (Ia-8a), R1When present, is fluorine.
In another embodiment of formulae (Ia-1) to (Ia-8a), R4When present, is selected from:
Figure BDA0003493730300000171
in another embodiment of formulae (Ia-1) to (Ia-8a), R4When present, is selected from:
Figure BDA0003493730300000172
in another embodiment of formulae (Ia-1) to (Ia-8a), R4When present, is selected from:
Figure BDA0003493730300000173
in another embodiment of formulae (Ia-1) to (Ia-8a), R5When present, is hydrogen, halogen, C1-C4Alkyl or C1-C4A haloalkyl group. In another embodiment of formulae (Ia-1) to (Ia-8a), R5When present, is hydrogen, C1-C4Alkyl or C1-C4A haloalkyl group. In another embodiment of formulae (Ia-1) to (Ia-8a), R5When present, isHydrogen, methyl or trifluoromethyl.
In another embodiment of formulae (Ia-1) to (Ia-8a), R7When present, is hydrogen.
In another embodiment of formulae (Ia-1) to (Ia-8a), Q is selected from the group consisting of 6-membered aryl and 5-or 6-membered heteroaryl having 1,2 or 3 heteroatoms independently selected from N, O and S, wherein the aryl or heteroaryl is optionally substituted with 1,2,3, 4 or 5 heteroatoms independently selected from halogen, C1-C4Haloalkyl and C1-C4Substituted by a substituent of alkoxy. In another embodiment of formulae (Ia-1) to (Ia-8a), Q is selected from 6-membered aryl, optionally substituted with 1,2,3, 4 or 5 substituents independently selected from halogen.
In another embodiment of formulae (Ia-1) to (Ia-8a), Q is selected from:
Figure BDA0003493730300000181
Figure BDA0003493730300000191
in another embodiment of formulae (Ia-1) to (Ia-8a), Q is selected from:
Figure BDA0003493730300000192
in another embodiment of formulae (Ia-1) to (Ia-8a),
X1、X2、X3、X4、X5、X6when present, are as defined in the summary;
R1when present, is selected from hydrogen, halogen and cyano;
R4when present, is selected from:
Figure BDA0003493730300000201
R5when present, is selected from hydrogen, methyl and trifluoromethyl;
R7when present, is hydrogen; and is
Q is selected from:
Figure BDA0003493730300000202
Figure BDA0003493730300000211
or a salt thereof.
In another embodiment of formulae (Ia-1) to (Ia-8a),
X1、X2、X3、X4、X5、X6when present, are as defined in the summary;
R1when present, is selected from hydrogen, halogen and cyano;
R4when present, is selected from:
Figure BDA0003493730300000212
R5when present, is selected from hydrogen;
R7when present, is hydrogen; and is
Q is selected from:
Figure BDA0003493730300000221
or a salt thereof.
In another embodiment, the compound of formula (I) or salt thereof has formula (Ia-5),
Figure BDA0003493730300000222
wherein R is1、R4And Q is as in the summary of the inventionAs defined. Preferably, R1Is hydrogen, halogen or cyano. More preferably, R1Is hydrogen or fluorine. Preferably, R4Is 4-morpholino or dimethylamino. Preferably, Q is 6-membered aryl optionally substituted with 1,2,3, 4 or 5 independently selected from halogen, cyano, nitro, hydroxy, C1-C4Alkyl radical, C1-C4Haloalkyl, C1-C4Alkoxy radical, C3-C6Cycloalkyl, -NH2、-NH(C1-C4Alkyl), -N (C)1-C4Alkyl radical)2、-NH(C3-C6Cycloalkyl), -N (C)1-C4Alkyl) (C3-C6-cycloalkyl), -NHSO2(C1-C4Alkyl), -SC1-C4Alkyl, -S (O) C1-C4Alkyl, -SO2C1-C4Alkyl, -S (O) C1-C4-haloalkyl and-SO2C1-C4Haloalkyl, wherein said 6-or 10-membered aryl is optionally fused with a 4-to 7-membered heterocycloalkyl having 1 or 2 heteroatoms selected from O, S and N, and wherein the carbon of the heterocycloalkyl is optionally substituted with 1,2 or 3 substituents independently selected from halogen, cyano, nitro, hydroxy, oxo, C1-C4Alkyl radical, C3-C6Cycloalkyl radical, C1-C4Haloalkyl, C1-C4Alkoxy, -NH2、-NH(C1-C4Alkyl) and-N (C)1-C4Alkyl radical)2And any N in the heterocycloalkyl group is selected from hydrogen, C, where the valence allows1-C4Alkyl and C3-C6Cycloalkyl substituents. Preferably, Q is 1,2,3, 4 or 5 independently selected from halogen, C1-C4Alkyl radical, C1-C4A 6-membered aryl group substituted with a substituent of haloalkyl and cyano. Preferably, Q is selected from:
Figure BDA0003493730300000231
the compounds of the present invention can be prepared by a variety of procedures, some of which are described below. All substituents are as previously defined unless otherwise indicated.
The products of each step may be recovered by conventional means including extraction, evaporation, precipitation, chromatography, filtration, trituration, crystallization and the like. The procedure may require the protection of certain groups, such as hydroxyl, thiol, amino or carboxyl groups, to minimize unwanted reactions. The selection, use and removal of protecting Groups is well known and considered standard practice, for example in T.W.Greene and P.G.M.Wuts, Protective Groups in Organic Chemistry (John Wiley and Sons, 1991).
As used herein: AcOH refers to acetic acid; aq. refers to aqueous solution, br refers to broad peak, CH3CN is acetonitrile, CH2Cl2Refers to dichloromethane, d refers to doublet, dd refers to doublet, DIPEA refers to N-diisopropylethylamine, DMA refers to N, N-dimethylacetamide, DMF refers to N, N-dimethylformamide, DMSO refers to dimethylsulfoxide, ee: means enantiomeric excess, eq, equivalent, ES means electrospray ionization, EtOAc means EtOAc, EtOH means EtOH, HATU means 1- [ bis (dimethylamino) methylene]-1H-1,2, 3-triazolo [4,5-b]Pyridinium 3-oxide hexafluorophosphate, HPLC for HPLC, iPrOH for isopropanol, J for coupling constant, KOAc for potassium acetate, K2CO3Refers to potassium carbonate, LCMS refers to liquid chromatography-mass spectrometry, m/z: refers to the mass to charge ratio, M refers to the molar concentration, M refers to the multiplet, MeOH refers to mEtOH, min refers to min, NaHCO3Is sodium bicarbonate, Na2CO3Is sodium carbonate, NEt3Refers to triethylamine, NMR refers to nuclear magnetic resonance, NMP refers to N-methylpyrrolidone, PEG refers to polyethylene glycol, q refers to a quartet, quin refers to a quintet, rt refers to rt, RtRefers to retention time, s refers to singlet, sat refers to saturation, T refers to temperature, T refers to triplet, td refers to triplet, THF refers to THF, wt refers to weight, and δ refers to chemical shift.
Scheme A
Figure BDA0003493730300000241
Scheme a depicts the reaction of a compound of formula (1) with a compound of formula (2) to give a compound of formula (Ia). The depicted compounds of formula (1) are those in which the radical A1Is a hydroxyl group or an activating group as discussed below, and Q, M, X1、X2、X3、X4、X5And X6Q, M, X as required in or to give a compound of formula (Ia)1、X2、X3、X4、X5And X6A group of (1). For example, a compound of formula (1) may be a compound wherein the depicted group "Q" is halogen, which is further processed in a subsequent step not shown to give a compound wherein Q is as defined in formula (Ia). Also for example, compounds wherein M is O may be further processed to compounds wherein M is S or wherein M is NR13The compound of (1). The preparation of such compounds of formula (1) is well understood in the art. The compound of formula (2) is a compound wherein R is7、n、Y1、Y2、Z1、Z2、Z3And Z4R required for or to produce a product of formula (Ia)7、Y1、Y2、Z1、Z2、Z3And Z4A group of (1). The preparation of such compounds of formula (2) is well understood in the art.
Scheme a depicts the reaction of a compound of formula (1) using a compound of formula (2) to give a compound of formula (Ia), as described above. Typical groups A1Is a hydroxyl or leaving group such as chlorine, bromine or imidazole, an activated moiety, another mixed anhydride of a carboxylic acid such as formic acid, acetic acid, or another moiety representing a symmetrical anhydride formed by two compounds of formula (1). For example, standard amide forming conditions may be used, such as those using coupling agents, including those used in peptide coupling, such as 2- (1H-7-azabenzotriazol-1-yl) -1,1,3, 3-tetramethyleMethyl ammonium Hexafluorophosphate (HATU), Dicyclohexylcarbodiimide (DCC) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide HCl. Additives such as 4- (dimethylamino) pyridine, 1-hydroxybenzotriazole, and the like may be used to facilitate the reaction if needed or desired. Such reactions typically employ a base such as N-methylmorpholine or NEt3In a variety of suitable solvents such as CH2Cl2DMF, NMP, DMA, THF, etc. Such reactions are well understood and appreciated in the art.
One of ordinary skill in the art will recognize that the compounds of formula (Ia) can be processed in a variety of ways to provide other compounds of formula (Ia). Such reactions include hydrolysis, oxidation, reduction, alkylation, arylation (including heteroaryl groups), amidation, sulfonation, and the like.
In addition, in an optional step not shown, the compound of formula (Ia) may be converted to a salt by methods well known and understood in the art.
Scheme B
Figure BDA0003493730300000261
Scheme B depicts the reaction of a compound of formula (3) with a compound of formula (4) to give a compound of formula (Ib). Among the depicted compounds of formula (3), Q, R7、X1、X2、X3、X4、X5And X6Q, R as required in the final compound of formula (I) or as required to give the final compound of formula (Ib)7、X1、X2、X3、X4、X5And X6A group of (1). For example, a compound of formula (3) may be a compound wherein the depicted group "Q" is halogen, which is further processed in a subsequent step not shown to give a compound wherein Q is as defined in formula (Ib). The preparation of such compounds of formula (3) is well understood in the art. The compounds of the formula (4) are those in which the radical A2Is a carboxyl group or an activating group as discussed below, and n, Y1、Y2、Z1、Z2、Z3And Z4Y required for, or to give, e.g. the final product of formula (Ib)1、Y2、Z1、Z2、Z3And Z4A group of (1). The preparation of such compounds of formula (4) is well understood in the art.
As noted above, scheme B depicts the reaction of a compound of formula (3), wherein a compound of formula (4) is used to give a compound of formula (Ib). Typical groups A2Is a carboxylic or acid chloride or bromide, or an imidazide, an activated moiety, a mixed anhydride of another carboxylic acid such as formic acid, acetic acid, or another moiety representing a symmetrical anhydride formed from two compounds of formula (4) wherein A is2Is a carboxyl derivative or another activated moiety. Such reactions typically employ a base such as N-methylmorpholine or triethylamine in a number of suitable solvents such as CH2Cl2DMF, N-methylpyrrolidone (NMP), DMA, THF, etc. It is well known that compounds of formula (Ib) wherein M is O can be further processed to compounds wherein M is S or wherein M is NR13The compound of (1).
Scheme C
Figure BDA0003493730300000271
Scheme C depicts the reaction of a compound of formula (5) with a compound of formula (6) to give a compound of formula (Ib). The depicted compound of formula (5) is the same as the compound of formula (3) described in scheme B. The compounds of formula (6) are those wherein R is depicted7And n, Y1、Y2、Z1、Z2、Z3And Z4Depicted R as required in or to produce a final product of formula (Ib)7And Y1、Y2、Z1、Z2、Z3And Z4A group of (1). The preparation of such compounds of formula (6) is well understood in the art. Using phosgene, carbonyldiimidazole, isopropenylcarbamate and optionally substituted phenoxycarbonyl halides, e.g. p-nitroPhenoxycarbonyl chloride is known to form asymmetric ureas.
Such reactions are generally carried out by adding phosgene, carbonyldiimidazole, isopropenylcarbamate and optionally substituted phenoxycarbonyl halide in a sequential manner to a compound of formula (5) or a compound of formula (6) using a base such as N-methylmorpholine or triethylamine in a number of suitable solvents such as CH2Cl2DMF, N-methylpyrrolidone (NMP), DMA, THF, etc. Then the other of compound (5) or compound (6) is added.
One of ordinary skill in the art will recognize that in schemes B and C, the compounds of formula (Ib) can be processed in a variety of ways to give other compounds of formula (Ib). Such reactions include hydrolysis, oxidation, reduction, alkylation, arylation (including heteroaryl groups), amidation, sulfonation, and the like. It is well known that compounds of formula (Ib) wherein M is O can be further processed to compounds wherein M is S or wherein M is NR13The compound of (1).
In addition, in an optional step not shown, the compounds of formula (Ib) may be converted into salts by methods well known and understood in the art.
The following examples are intended to illustrate, not to limit, and represent specific embodiments of the present invention.
Analytical methods a and B were performed using an Agilent 1200 infinite series Liquid Chromatography (LC) system consisting of a 1260HiP degasser (G4225A), 1260 binary pump (G1312B), 1290 autosampler (G4226A), 1290 thermostatted column compartment (G1316C), and 1260 diode array detector (G4212B) coupled to an Agilent 6150 single quadrupole Mass Spectrometry (MS) detector. The injection amount is set to 1 μ L by default. UV (DAD) acquisition was performed at 40Hz with a scanning range of 190 and 400nm (step size 5 nm). A 1:1 split was used before the MS detector. The MS was operated in positive and negative ion mode using an electrospray ionization source (ESI). The atomizer pressure was set at 50psi and the drying gas temperature and flow were set at 350 deg.C and 12L/min, respectively. The capillary voltage used was 4000V in the positive mode and 3500V in the negative mode. In both polarity modes, the MS acquisition range is set to be 100-800m/z, and the step size is 0.2 m/z. Fragmentation voltage was set to 70(ESI +) or 120(ESI-), gain was set to 0.40(ESI +) or 1.00(ESI-), and ion count threshold was set to 4000(ESI +) or 1000 (ESI-). The total MS scan cycle time is 0.15 seconds/cycle. Data acquisition was performed using Agilent Chemstation software.
The method A comprises the following steps: analysis was carried out on a Phenomenex Gemini-NX C18 column 50mm long, 2.1mm internal diameter and 3 μm particle size. The mobile phases used were: a1 ═ water containing 0.1% formic acid/B1 ═ CH containing 0.1% formic acid3And (C) CN. The run was carried out at a temperature of 50 ℃ and a flow rate of 1.2mL/min, with a gradient elution of from 5% to 95% (B1) in 1.5 minutes, then at 95% (B1) for 0.5 minutes.
The method B comprises the following steps: the analysis was carried out on a Waters Xbridge C18 column 50mm long, 2.1mm internal diameter and 3.5 μm particle size. The mobile phases used were: a 2-water with 10mM ammonium bicarbonate, pH adjusted to 9/B2-CH with ammonium hydroxide3And (C) CN. The run was performed at a temperature of 50 ℃ and a flow rate of 1.2mL/min, and the gradient elution was a gradient from 5% to 95% (B2) over 1.5 minutes, followed by a hold at 95% (B2) for 0.5 minutes.
Analytical methods C and D were performed using a Waters Acquity UPLC Liquid Chromatography (LC) system coupled to a Waters SQ Detector 2 single quadrupole Mass Spectrometry (MS) Detector. The UV (DAD) acquisition was performed with a scan range of 200 and 400nm (resolution of 1.2 nm). The MS was operated in positive and negative ion mode using an electrospray ionization source (ESI). The capillary voltage is 3.50(kV), the taper hole voltage is 35(V), and the desolventizing temperature is 550 ℃. The desolvation gas flow rate was 1000(L/Hr), and the cone orifice gas flow rate was 50 (L/Hr). The MS collection range is set to be 100-1500 m/z. The MS scan cycle time is 0.5 seconds. Data acquisition was performed using Waters Masslynx software.
The method C comprises the following steps: the analysis was carried out on an Acquity UPLC BEH C18 column 50mm long, 2.1mm internal diameter and 1.7 μm particle size. The mobile phases used were: a1 ═ water containing 0.1% formic acid/B1 ═ CH containing 0.1% formic acid3And (C) CN. The injection amount was 0.1. mu.L. The run was performed with gradient elution at a temperature of 40 ℃ and a flow rate of 0.6 mL/min. Method information (time (min) and B%): 0 to 5; 0.3 to 5; 2.5-95; 3.7-95; 4-5; 4.6-5.
The method D comprises the following steps: the analysis was performed on an Acquity UPLC BEH C18 column,the column had a length of 50mm, an inner diameter of 2.1mm and a particle size of 1.7 μm. The mobile phases used were: a1 ═ water containing 10mM ammonium acetate/B1 ═ CH containing 0.1% formic acid3And (C) CN. The injection amount was 0.1. mu.L. The run was performed with a gradient elution at a temperature of 45 ℃ and a flow rate of 0.5 mL/min. Method information (time (min) and a%): 0 to 98; 0.3 to 98; 3.2-2; 4.4-2; 4.7-98.
Example 1.1
N- [8- (3, 5-dichlorophenyl) -4- (dimethylamino) -3-quinolinyl ] -2, 3-dihydro-1, 4-benzoxazine-4-carboxamide
Figure BDA0003493730300000291
To a stirred solution of 8-bromoquinolin-4-ol (2g, 8.82mmol) in propionic acid (20mL, 265mmol) at 100 deg.C was slowly added nitric acid (1mL, 16mmol) over 5 minutes. The reaction was heated to 125 ℃ and stirred for 45 minutes. The reaction was then allowed to cool to room temperature, allowing the product to precipitate. The solid was collected by filtration and washed with water (3X 10mL), iPrOH (10mL), isohexane (10mL), then dried in a vacuum oven for 1 hour to give 8-bromo-3-nitro-quinolin-4-ol. LCMS (method B): rt＝0.54min，m/z＝269[M+H]+。
To a solution of 8-bromo-3-nitro-quinolin-4-ol (1.52g, 5.37mmol) was added POCl3(10mL, 107 mmol). The suspension was heated to reflux and stirred for 2 hours. The reaction mixture was allowed to cool to room temperature and left overnight. The reaction mixture was concentrated in vacuo (azeotroped with toluene) to give 8-bromo-4-chloro-3-nitro-quinoline, which was used directly in the next step without further purification.
To a solution of 8-bromo-4-chloro-3-nitro-quinoline (2.32g, 5.38mmol) in THF (30mL) was slowly added dimethylamine (2M in THF, 7mL, 14 mmol). The reaction was allowed to stir at room temperature for 1.5 hours. The reaction mixture was washed with EtOAc and saturated NaHCO3The aqueous solution (50mL each) was partitioned between. Brine (50mL) was added. The layers were separated and the aqueous layer was extracted with EtOAc (2X 50 mL). The organic layers were combined and concentrated in vacuo to give 8-bromo-N, N-dimethyl-3-nitro-quinolin-4-amine. LCMS (method B): rt＝1.13min，m/z＝296[M+H]+。
To a solution of 8-bromo-N, N-dimethyl-3-nitro-quinolin-4-amine (505mg, 1.62mmol) was added (3, 5-dichlorophenyl) boronic acid (314mg, 1.61mmol), tetrakis (triphenylphosphine) palladium (0) (92mg, 0.08mmol), and Na2CO3(351mg, 3.28 mmol). Sealing the vial, then evacuating and applying N2Recharging for three times. 1, 4-dioxane (9mL) was added followed by water (3mL) and the reaction was heated to 100 ℃ in a microwave for 1 hour. The reaction mixture was washed with EtOAc and saturated NaHCO3The aqueous solution (50mL each) was partitioned between. The layers were separated and the aqueous layer was extracted with EtOAc (2X 25 mL). The organic layers were combined, concentrated in vacuo and the residue was purified by column chromatography to give 8- (3, 5-dichlorophenyl) -N, N-dimethyl-3-nitro-quinolin-4-amine. LCMS (method B): rt＝1.57min，m/z＝362[M+H]+。
To a stirred suspension of 8- (3, 5-dichlorophenyl) -N, N-dimethyl-3-nitro-quinolin-4-amine (401mg, 1.05mmol) in THF (5mL), EtOH (5mL) and water (2.5mL) were added iron (184mg,3.23mmol) and NH4Cl (168mg, 3.13 mmol). The reaction was heated to 75 ℃ and stirred for 45 minutes. The reaction was allowed to cool to room temperature and then saturated NaHCO3Partition between aqueous and EtOAc (25mL each). Passing the mixture through
Figure BDA0003493730300000301
Filtration (washing with EtOAc) and separation of the filtrate layers. The aqueous layer was extracted with EtOAc (2X 25mL) and the organic layers were combined and concentrated in vacuo. The residue was purified by column chromatography to give 8- (3, 5-dichlorophenyl) -N4, N4-dimethyl-quinoline-3, 4-diamine. LCMS (method B): rt＝1.48min，m/z＝363.2[M+H]+。
In N2To a stirred solution of 4-nitrophenyl chloroformate (88mg, 0.42mmol) in THF (2mL) at 0 deg.C under an atmosphere was added 8- (3, 5-dichlorophenyl) -N dropwise over 2 minutes4,N4-a solution of dimethyl-quinoline-3, 4-diamine (148mg, 0.42mmol) in THF (2.5 mL). The reaction was allowed to stir at 0 ℃ for 30 minutes. The reaction solution was used directly in the next step.
To the reaction mixture was added THF (0.5mL)3, 4-dihydro-2H-1, 4-benzoxazine (71mg, 0.51mmol) and NEt3(132. mu.L, 0.94 mmol). The reaction was stirred at room temperature overnight. The reaction mixture was washed with saturated NaHCO3Aqueous solution and CH2Cl2(20mL each). Separate the layers and use CH2Cl2The aqueous layer was extracted (2X 20 mL). The combined organic layers are passed through
Figure BDA0003493730300000313
And concentrated in vacuo. The crude product was purified by column chromatography to give the title compound. LCMS (method B): rt＝1.62min，m/z＝493.0[M+H]+。1H NMR(400MHz,CDCl3)δ[ppm]:9.95(s,1H),9.13(s,1H),7.91(quint,J＝4.8Hz,1H),7.55(d,J＝2Hz,1H),7.53(d,J＝5.2Hz,1H),7.43(dd,J＝1.6,8.4Hz,1H),7.38(t,J＝2Hz,1H),7.17(m,1H),7.01(m,2H),4.36(t,J＝4.4Hz,2H),4.02(t,J＝4.8Hz,2H),2.9(s,6H)。
Example 2.1
8- (3, 5-dichlorophenyl) -N- (2, 3-dihydro-1, 4-benzoxazin-4-yl) -4- (dimethylamino) -1, 7-naphthyridine-3-carboxamide
Figure BDA0003493730300000311
2-chloro-3-fluoro-pyridine-4-carboxylic acid (10.1g, 56.3mmol) and SOCl2(40mL, 547mmol) of the mixture was heated at 80 ℃ for 2 hours. The reaction was allowed to cool to room temperature and concentrated in vacuo. It was used directly in the next step: toluene (145mL) and NEt were added3(9.8mL, 70mmol) followed by the addition of ethyl 3- (dimethylamino) -prop-2-enoate (10.2g, 69.6 mmol). The reaction was heated and stirred at 80 ℃ for 45 minutes. The mixture was allowed to cool to room temperature and passed
Figure BDA0003493730300000312
Filter (wash with EtOAc). The filtrate was concentrated in vacuo and the residue partitioned between EtOAc and 2M aqueous HCl (150mL each). The layers were separated and the aqueous layer was extracted with EtOAc (150 mL). The combined organic layers were over anhydrous MgSO4Drying, filtering, and vacuum concentrating to obtain2- (2-chloro-3-fluoro-pyridine-4-carbonyl) -3- (dimethylamino) -prop-2-enoic acid ethyl ester. LCMS (method B): rt＝0.86min，m/z＝301.00[M+H]+。
To a solution of ethyl 2- (2-chloro-3-fluoro-pyridine-4-carbonyl) -3- (dimethylamino) -prop-2-enoate (188mg, 0.59mmol) in diethyl ether (2.4mL) and EtOH (0.6mL) was added 4-methoxybenzylamine (94. mu.L, 0.71 mmol). The reaction mixture was stirred at room temperature for 15 minutes, and a precipitate was formed. The reaction mixture was concentrated in vacuo to give a residue. The residue was triturated with cyclohexane to give 2- (2-chloro-3-fluoro-pyridine-4-carbonyl) -3- [ (4-methoxyphenyl) methyl-amino]-prop-2-enoic acid ethyl ester. LCMS (method B): rt＝1.21min，m/z＝393[M+H]+。
To 2- (2-chloro-3-fluoro-pyridine-4-carbonyl) -3- [ (4-methoxyphenyl) methyl-amino at room temperature]Addition of K to a solution of ethyl-prop-2-enoate (214mg, 518. mu. mol) in DMF (2.6mL)2CO3(230mg, 1.66 mmol). The reaction mixture was heated and stirred at 40 ℃ for 2 hours. After cooling to room temperature, the reaction mixture was poured into ice water (20mL) to form a fine precipitate. The precipitate was dissolved in EtOAc (20mL) and the layers were separated. The aqueous layer was extracted with EtOAc (2X 10mL), and the combined organic layers were washed with water (20mL) and anhydrous MgSO4Drying, filtering and vacuum concentrating to obtain 8-chloro-1- [ (4-methoxyphenyl) methyl]-4-oxo-1, 7-naphthyridine-3-carboxylic acid ethyl ester. LCMS (method B): rt＝1.01min，m/z＝373[M+H]+。
(3, 5-dichlorophenyl) boronic acid (110mg, 0.56mmol) and 1,1' -bis (diphenylphosphino) ferrocene-Pd (II) CH2Cl2Complex and Na2CO3(100mg, 0.93mmol) were mixed. Sealing the vial, then evacuating and applying N2And (6) recharging. Then, 8-chloro-1- [ (4-methoxyphenyl) methyl group in 1, 4-dioxane (2.4mL, 28mmol) was added]-4-oxo-1, 7-naphthyridine-3-carboxylic acid ethyl ester (186mg, 0.47mmol), then water (0.8mL) was added and the reaction mixture was heated in a microwave at 100 ℃ for 1 hour. By passing
Figure BDA0003493730300000321
Filtration reactionThe mixture was washed with EtOAc. The filtrate was washed with water (20mL) and anhydrous MgSO4Drying, filtering and vacuum concentrating, then purifying by column chromatography to obtain 8- (3, 5-dichlorophenyl) -1- [ (4-methoxyphenyl) methyl]-4-oxo-1, 7-naphthyridine-3-carboxylic acid ethyl ester. LCMS (method B): rt＝1.30min，m/z＝483[M+H]+。
To 8- (3, 5-dichlorophenyl) -1- [ (4-methoxyphenyl) methyl]-4-oxo-1, 7-naphthyridine-3-carboxylic acid ethyl ester (877mg, 1.72mmol) in CH2Cl2To a solution in (9mL) was added anisole (1mL, 1.74mmol) followed by TFA (2.5mL, 33 mmol). The resulting reaction mixture was stirred at room temperature for 1 hour, then concentrated in vacuo. To the crude product was added saturated NaHCO3A mixture of aqueous solution and EtOAc (25mL each) and the resulting suspension was stirred vigorously for 15 minutes. The precipitate was isolated by filtration (washed with water then EtOAc) and dried in a vacuum oven to give ethyl 8- (3, 5-dichlorophenyl) -4-hydroxy-1, 7-naphthyridine-3-carboxylate. LCMS (method B): rt＝0.9min，m/z＝363[M+H]+。
To a stirred solution of ethyl 8- (3, 5-dichlorophenyl) -4-hydroxy-1, 7-naphthyridine-3-carboxylate (61mg, 0.13mmol) in CH2Cl2To the suspension in (2mL) was added oxalyl chloride (17. mu.L, 192. mu. mol), followed by DMF (1. mu.L, 13. mu. mol), and the resulting mixture was stirred at room temperature for 45 minutes. By adding saturated NaHCO3The reaction was quenched with aqueous solution (5mL) and the mixture was washed with water and CH2Cl2(10mL each). Separate the layers and use CH2Cl2The aqueous layer was extracted. The combined organic layers were over anhydrous MgSO4Drying, filtering and vacuum concentrating to obtain 4-chloro-8- (3, 5-dichlorophenyl) -1, 7-naphthyridine-3-ethyl formate. LCMS (method B): rt＝1.6min，m/z＝381[M+H]+。
To a microwave vial was added 4-chloro-8- (3, 5-dichlorophenyl) -1, 7-naphthyridine-3-carboxylic acid ethyl ester (59mg, 0.12mmol) and dimethylamine-HCl (17mg, 0.2mmol) in 1, 4-dioxane (0.5 mL). The vial was sealed, DIPEA (73. mu.L, 0.41mmol) was added and the reaction mixture was heated in a microwave at 100 ℃ for 30 minutes. The mixture was diluted with EtOAc (10mL)With saturated NaHCO3The aqueous solution (10mL) and brine (10mL) were washed with anhydrous MgSO4Drying, filtering and vacuum concentrating to obtain 8- (3, 5-dichlorophenyl) -4- (dimethylamino) -1, 7-naphthyridine-3-carboxylic acid ethyl ester. LCMS (method B): rt＝1.5min，m/z＝390[M+H]+。
To a stirred solution of ethyl 8- (3, 5-dichlorophenyl) -4- (dimethylamino) -1, 7-naphthyridine-3-carboxylate (556mg, 1.35mmol) in THF (14mL) was added a solution of lithium hydroxide (99mg, 4.05mmol) in water (4.5mL) and MeOH (4.5 mL). The reaction mixture was heated at 40 ℃ for 2 hours and stirred at room temperature overnight. The mixture was then concentrated in vacuo and the residue was taken up in water (25 mL). The aqueous layer was washed with EtOAc (25mL) and then the pH was adjusted to 4 by the addition of 2M aqueous HCl to form a suspension. The precipitate was isolated by filtration and dried in a vacuum oven overnight to give 8- (3, 5-dichlorophenyl) -4- (dimethylamino) -1, 7-naphthyridine-3-carboxylic acid as a solid. LCMS (method B): rt＝0.78min，m/z＝362[M+H]+。
At room temperature in N2To a solution of 3, 4-dihydro-2H-1, 4-benzoxazine (504mg, 3.73mmol) in EtOH (4mL) was added sodium nitrite (309mg, 4.48mmol) in water (1.6mL) under an atmosphere. The mixture was then cooled to 0 ℃. Concentrated HCl (0.39mL, 4.7mmol) was added dropwise to the reaction at 0 ℃. The reaction was then stirred at 0 ℃ for 15 minutes.
A solution of sodium hydroxide (1.43g, 35.87mmol) in water (3.7mL) was added at 0 deg.C followed by sodium dithionite (2.40g, 11.75 mmol). The resulting suspension was heated to 90 ℃ for 2 hours and then cooled to room temperature.
The reaction was diluted with water (30mL) and then extracted with toluene (30mL) and EtOAc (15 mL). The combined organic layers were separated and concentrated in vacuo. The residue was purified by column chromatography to give 2, 3-dihydro-1, 4-benzoxazin-4-amine (354mg) as a pale yellow oil. LCMS (method B) Rt＝0.63min，m/z＝151[M+H]+。
To a stirred suspension of 8- (3, 5-dichlorophenyl) -4- (dimethylamino) -1, 7-naphthyridine-3-carboxylic acid (158mg, 0.41mmol) in DMF (5mL) was added NEt3(0.25mL, 1.8mmol) followed by 2, 3-dihydro-1, 4-benzoxazin-4-amine (79mg, 0.501mmol) and PyBOP (341mg, 0.64 mmol). The reaction was allowed to proceed at room temperature under N2Stirred under atmosphere for 48 hours. The reaction was diluted with brine (25mL) and CH2Cl2(3X 15 mL). The combined organic layers were separated and concentrated in vacuo. The residue was purified by column chromatography to give the title compound. LCMS (method B) Rt＝1.35min，m/z＝494[M+H]+。1H NMR(400MHz,DMSO-d6)δ[ppm]:10.7(s,1H),8.90(s,1H),8.67(d,J＝4.4Hz,1H),8.1(m,2H),7.75(t,J＝2Hz,1H),7.03(dd,J＝8,1.2Hz,1H),6.85(td,J＝2,8Hz,1H),6.69-6.78(m,2H),4.38(t,J＝4.4Hz,2H),3.68(s,2H),3.13(s,6H)。
The following compounds were prepared analogously by the method of example 2.1:
Figure BDA0003493730300000341
Figure BDA0003493730300000351
Figure BDA0003493730300000361
example 3.1
8- (3, 5-dichlorophenyl) -N- (2, 3-dihydro-1, 4-benzoxazin-4-yl) -4- (dimethylamino) -1, 5-naphthyridine-3-carboxamide
Figure BDA0003493730300000371
To 3, 4-dichloropyridine-2-carboxylic acid (3.96g, 20.6mmol) was added thionyl chloride (15mL, 205mmol) and the reaction mixture was heated to 80 ℃ for 1 hour. The reaction was allowed to cool to room temperature and concentrated in vacuo to afford 3, 4-dichloropyridine-2-carbonyl chloride, which was used in the next step without further purification.
To the stirred 3, 4-dichloropyridine-2-To a solution of phosgene (20.6mmol, 4.76g) in toluene (50mL) was added NEt3(3.5mL, 25mmol) followed by the addition of ethyl 3- (dimethylamino) prop-2-enoate (3.6mL, 25 mmol). The reaction was stirred at room temperature overnight. By passing
Figure BDA0003493730300000372
The reaction was filtered (washed with EtOAc). The filtrate was concentrated in vacuo, and the residue was partitioned between EtOAc and 1M aqueous HCl (100mL each). The layers were separated and the aqueous layer was extracted with EtOAc (50 mL). The combined organic layers were concentrated in vacuo to give ethyl 2- (3, 4-dichloropyridine-2-carbonyl) -3- (dimethylamino) prop-2-enoate. LCMS (method B) Rt＝0.88min，m/z＝317.0[M+H]+。
To a stirred solution of ethyl 2- (3, 4-dichloropyridine-2-carbonyl) -3- (dimethylamino) prop-2-enoate (5.58g, 12.7mmol) in diethyl ether (50mL) and EtOH (12mL) was added 4-methoxybenzylamine (1.9mL, 14 mmol). The reaction was allowed to stir at room temperature for 2 hours. The reaction mixture was diluted with water (100 mL). Separate the layers and use CH2Cl2The aqueous layer was extracted (3X 50 mL). The combined organic layers were washed with anhydrous Na2SO4Drying, filtering and vacuum concentrating to obtain 2- (3, 4-dichloropyridine-2-carbonyl) -3- [ (4-methoxyphenyl) methylamino]2-propenoic acid ethyl ester.
2- (3, 4-dichloropyridine-2-carbonyl) -3- [ (4-methoxyphenyl) methylamino]Ethyl prop-2-enoate (5.92g, 9.40mmol) was dissolved in DMF (24 mL). Adding K2CO3(4.0g, 28.9mmol) and the mixture was stirred at 90 ℃ for 6 h. The reaction mixture was cooled to room temperature, quenched by addition of water (250mL) and quenched with CH2Cl2(100mL) dilution. Separate the layers and use CH2Cl2The aqueous layer was extracted (2X 50 mL). The combined organic layers are passed through
Figure BDA0003493730300000381
Filtered, then washed with brine (100mL), anhydrous Na2SO4Dry, filter and reduce to dryness in vacuo. By chromatography (0-6% MeOH/CH)2Cl2) Purifying the crude material to obtain 8-hydroxy-1- [ (4-methoxybenzene)Radical) methyl]-4-oxo-1, 5-naphthyridine-3-carboxylic acid ethyl ester.
Reacting 8-hydroxy-1- [ (4-methoxyphenyl) methyl]-4-oxo-1, 5-naphthyridine-3-carboxylic acid ethyl ester (840mg, 1.09mmol) dissolved in CH2Cl2(11mL) and DMF (0.05 mL). To the mixture was added oxalyl chloride (0.48mL, 5.5mmol) and the mixture was heated to reflux for 3 hours. The reaction mixture was cooled and purified by addition of saturated NaHCO3Aqueous solution (50 mL). Separate the layers and use CH2Cl2The aqueous layer was extracted (2X 25 mL). The combined organic layers were reduced in vacuo to give 4, 8-dichloro-1, 5-naphthyridine-3-carboxylic acid ethyl ester.
Ethyl 4, 8-dichloro-1, 5-naphthyridine-3-carboxylate (950mg, 2.21mmol) was dissolved in THF (5 mL). To this solution dimethylamine (2mol/L) in THF (1.1mL, 2.2mmol, 2M) was added dropwise and the mixture was stirred at rt for 30 min. The crude reaction mixture was concentrated and the residue was purified by column chromatography (20-50% EtOAc/cyclohexane) to give 8-chloro-4- (dimethylamino) -1, 5-naphthyridine-3-carboxylic acid ethyl ester. LCMS (method B) Rt＝1.07min，m/z＝280.0[M+H]+。
Ethyl 8-chloro-4- (dimethylamino) -1, 5-naphthyridine-3-carboxylate (315mg, 0.93mmol) was dissolved in 1, 4-dioxane (3mL) and water (1 mL). To this mixture was added [1,1' -bis (diphenylphosphino) ferrocene]Palladium (II) dichloride (40mg, 0.048mmol), followed by addition of (3, 5-dichlorophenyl) boronic acid (215mg, 1.13mmol) and Na2CO3(300mg, 2.83 mmol). The mixture was subjected to microwave irradiation at 100 ℃ for 1 hour. The crude reaction mixture was concentrated and the residue was purified by column chromatography (5-40% EtOAc/cyclohexane) to give ethyl 8- (3, 5-dichlorophenyl) -4- (dimethylamino) -1, 5-naphthyridine-3-carboxylate. LCMS (method B) Rt＝1.56min，m/z＝390.0[M+H]+。
To a stirred solution of ethyl 8- (3, 5-dichlorophenyl) -4- (dimethylamino) -1, 5-naphthyridine-3-carboxylate (272mg, 0.65mmol) in 1, 4-dioxane (2mL) was added lithium hydroxide (32mg, 1.34mmol) in water (2 mL). The reaction was heated to 100 ℃ overnight. Then, the reaction mixture was cooled to room temperature. The reaction mixture was quenched by the addition of water (50mL) and EtOAc (50 mL).The pH was adjusted to pH 4 with 2M HCl. The layers were separated and the aqueous layer was extracted with EtOAc (2X 50 mL). The combined organic layers were washed with brine, over anhydrous Na2SO4Drying, filtering and vacuum decrement to obtain 8- (3, 5-dichlorophenyl) -4- (dimethylamino) -1, 5-naphthyridine-3-formic acid. LCMS (method B) Rt＝0.82min，m/z＝362.0[M+H]+。
A mixture of 2, 3-dihydro-1, 4-benzoxazin-4-amine (0.115g, 0.73mmol) and PyBOP (0.63g, 1.21mmol) was placed in N2Treated under atmosphere and with a solution of 8- (3, 5-dichlorophenyl) -4- (dimethylamino) -1, 5-naphthyridine-3-carboxylic acid (0.24g, 0.67mmol) in THF (3mL) followed by NEt3(0.42mL, 3 mmol). The resulting reaction mixture was allowed to stir at room temperature for more than 48 hours. By adding saturated NaHCO3The reaction mixture was quenched with aqueous solution (100mL) and CH2Cl2(50mL) dilution. Separate the layers and use CH2Cl2The aqueous layer was extracted (2X 25 mL). The combined organic layers were washed with anhydrous Na2SO4Dried, filtered, and then reduced in vacuo. The crude product was purified by column chromatography (10-50% EtOAc/cyclohexane) to afford the title compound. LCMS (method B) Rt＝1.39min，m/z＝494.0[M+H]+。1H NMR(400MHz,CDCl3)δ[ppm]:9.62(s,1H),9.24(s,1H),8.96(d,J＝4.4Hz,1H),7.59(m,3H),7.47(t,J＝2Hz,1H),6.79-6.95(m,4H),4.50(t,J＝4.4Hz,2H),3.74(t,J＝4.8Hz,2H),3.35(s,6H)。
The following compounds were prepared analogously by the method of example 3.1:
Figure BDA0003493730300000391
Figure BDA0003493730300000401
example 4.1
5- (3, 5-dichlorophenyl) -N- (2, 3-dihydro-1, 4-benzoxazin-4-yl) -1- (dimethylamino) naphthalene-2-carboxamide
Figure BDA0003493730300000402
For a mixture containing 1-bromo-5-nitro-naphthalene (1.04g, 4.13mmol), (3, 5-dichlorophenyl) boronic acid (0.7g, 3.6mmol), and Na2CO3(0.86g, 8.10mmol) and [1,1' -bis (diphenylphosphino) ferrocene]A round-bottomed flask containing a mixture of dichloropalladium (II) (156mg, 0.20mmol) was evacuated and charged with N2Recharging for three times. The reaction mixture was treated with 1, 4-dioxane (20mL) and degassed water (6mL), heated to 80 ℃ and stirred for 45 minutes. The mixture was then allowed to cool to room temperature, then diluted with water (40mL) and CH2Cl2(3X 30 mL). The combined organic layers were over anhydrous MgSO4Dried, filtered and concentrated in vacuo. The crude product was purified by column chromatography, appropriate fractions were combined and concentrated in vacuo to give 1- (3, 5-dichlorophenyl) -5-nitro-naphthalene.
Mixing 1- (3, 5-dichlorophenyl) -5-nitro-naphthalene (928mg, 2.77mmol), NH4A mixture of Cl (0.47g, 8.72mmol) and iron (0.47g, 8.28mmol) was placed in N2Under atmosphere, it was then treated with THF (14mL), EtOH (14mL) and water (7 mL). The resulting mixture was heated to 75 ℃ and allowed to stir for 45 minutes. The mixture was then allowed to cool to room temperature and then passed
Figure BDA0003493730300000403
Filtration (with CH)2Cl2Washing). The filtrate was concentrated in vacuo and taken up with saturated NaHCO3Aqueous solution (50mL) and CH2Cl2(3X 25 mL). The combined organic layers were over anhydrous MgSO4Drying, filtering and vacuum concentrating to obtain 5- (3, 5-dichlorophenyl) naphthalene-1-amine. LCMS (method B) Rt＝1.49min，m/z＝288.0[M+H]+。
A solution of 5- (3, 5-dichlorophenyl) naphthalen-1-amine (881mg, 2.60mmol) in DMF (10mL) was placed in N2Cooled to about-5 ℃ over an ice/salt bath under an atmosphere and treated with N-bromosuccinimide (474mg, 2.58 mmol). Then saturated NaHCO3The resulting reaction mixture was treated with aqueous solution (50mL) to form a light brown precipitate. CH for the mixture2Cl2(3X 30mL) and the combined organic layers were concentrated in vacuo. The residue was purified by column chromatography to give 2-bromo-5- (3, 5-dichlorophenyl) naphthalen-1-amine. LCMS (method B) Rt＝1.64min，m/z＝365.8[M+H]+。
A suspension of 2-bromo-5- (3, 5-dichlorophenyl) naphthalen-1-amine (0.73g, 1.79mmol) in formic acid (6mL, 160mmol) was placed in N2Under an atmosphere and treated with formaldehyde solution (37 wt% in water; 110mmol, 8 mL). The resulting suspension was warmed to 100 ℃ and allowed to stir for 1 hour. The reaction mixture was allowed to cool to room temperature and then saturated NaHCO was added carefully3Aqueous solution (60 mL). Then using CH2Cl2The mixture was extracted (3X 20mL) and the combined organic layers were over anhydrous MgSO4Dried, filtered, and concentrated in vacuo. The residue was purified by column chromatography to give 2-bromo-5- (3, 5-dichlorophenyl) -N, N-dimethyl-naphthalen-1-amine. LCMS (method B) Rt＝1.93min，m/z＝393.8[M+H]+。
In a pressure vessel with MeOH (10mL), NEt3(0.54mL, 3.9mmol) and [1,1' -bis (diphenylphosphino) ferrocene]A solution of 2-bromo-5- (3, 5-dichlorophenyl) -N, N-dimethyl-naphthalen-1-amine (532mg, 1.28mmol) in 1, 4-dioxane (10mL) was treated with dichloropalladium (II) (103mg, 134 μmol) and then stirred at 100 ℃ under a CO atmosphere (50psi) for 16 hours. The reaction mixture was then allowed to cool to room temperature, filtered, and concentrated in vacuo. The residue was purified by column chromatography to give methyl 5- (3, 5-dichlorophenyl) -1- (dimethylamino) naphthalene-2-carboxylate. LCMS (method B) Rt＝1.75min，m/z＝374.0[M+H]+。
A solution of methyl 5- (3, 5-dichlorophenyl) -1- (dimethylamino) naphthalene-2-carboxylate (421mg, 1.01mmol) in 1, 4-dioxane (15mL), water (5mL) and lithium hydroxide (512mg, 20.3mmol) was stirred at 80 ℃ for 48 hours. The reaction mixture was allowed to cool to room temperature and then treated with 2M HCl (17.5 mL-make the mixture weakly basic). CH for aqueous layer2Cl2(3X 25 mL). The combined organic layers were over anhydrous MgSO4Drying, filtering and vacuum concentrating to obtain 5- (3, 5-dichlorophenyl) -1- (dimethylamino) naphthalene-2-carboxylic acid. LCMS (method B) Rt＝1.10min，m/z＝358.0[M-H]-。
A mixture of 2, 3-dihydro-1, 4-benzoxazin-4-amine (0.082g, 519. mu. mol) and PyBOP (452mg, 869. mu. mol) was placed in N2Treated with a solution of 5- (3, 5-dichlorophenyl) -1- (dimethylamino) naphthalene-2-carboxylic acid (192mg, 426. mu. mol) in THF (3mL) under atmosphere and then NEt3(0.30mL, 2.2 mmol). The resulting reaction mixture was allowed to stir at room temperature overnight. The reaction mixture was diluted with water (15mL) and CH2Cl2(3X 15 mL). The combined organic layers were over anhydrous MgSO4Dried, filtered and concentrated in vacuo. The crude product was purified by column chromatography to give the title compound. LCMS (method B) Rt＝1.61min，m/z＝492.2[M+H]+。1H NMR(400MHz,DMSO)[ppm]:10.5(s,1H),8.36(d,J＝8.6Hz,1H),7.75(t,J＝2Hz,1H),7.64-7.68(m,1H),7.60-7.48(m,5H),6.98(dd,J＝8,1.4Hz,1H),6.86-6.80(m,1H),6.77(dd,J＝8,1.6Hz,1H),6.73-6.67(m,1H),4.38(t,J＝4.3Hz,2H),3.70-3.63(m,2H),2.99(s,6H)。
Example 5.1
8- (3, 5-dichlorophenyl) -N- (2, 3-dihydro-4H-benzo [ b ] [1,4] oxazin-4-yl) -4- (dimethylamino) quinoline-3-carboxamide
Figure BDA0003493730300000421
A solution of 2-bromoaniline (7.96g, 44.9mmol) and diethyl 2- (ethoxymethylene) malonate (11mL, 53.8mmol) was heated to 125 ℃ for 1 hour. LCMS (method B) Rt＝1.28min，m/z＝342.0
[M+H]+. Diphenyl ether (100mL) was added and the reaction was heated to 250 ℃ and stirred for 48 hours. The reaction was allowed to cool to room temperature and a precipitate formed. Diethyl ether (100mL) was added, the precipitate was isolated by filtration (washed with diethyl ether),
and vacuum dried to obtain 8-bromo-4-hydroxy-quinoline-3-carboxylic acid ethyl ester. LCMS (method B) Rt＝0.69，m/z＝296.0[M+H]+。
8-bromo-4-hydroxy-quinoline-3-carboxylic acid ethyl ester (2.0g, 6.42mmol) in CH2Cl2(20mL) inIs placed in N2Treated with oxalyl chloride (0.60mL, 6.8mmol) and DMF (0.02mL) under atmosphere. The reaction mixture was warmed to 50 ℃ and allowed to stir for 45 minutes. The reaction mixture was allowed to cool to room temperature and then concentrated in vacuo to afford 8-bromo-4-chloro-quinoline-3-carboxylic acid ethyl ester. LCMS (method B) Rt＝1.28min，m/z＝314.0[M+H]+。
In N2To 8-bromo-4-chloro-quinoline-3-carboxylic acid ethyl ester (2.13g, 6.42mmol) was added dimethylamine (2M) in THF (13mL) under an atmosphere. The resulting mixture was warmed to 60 ℃ and allowed to stir for 15 minutes. The reaction mixture was concentrated in vacuo and then saturated NaHCO3Aqueous solution (40mL) treated with EtOAc (3 flex)
30 mL). The combined organic layers were over anhydrous MgSO4Dried and concentrated in vacuo. The residue was subjected to column chromatography (20-60% EtOAc/cyclohexane) to afford 8-bromo-4- (dimethylamino) quinoline-3-carboxylic acid ethyl ester. LCMS (method B) Rt＝1.23min，m/z＝323.0[M+H]+。
In N2Under the atmosphere, ethyl 8-bromo-4- (dimethylamino) quinoline-3-carboxylate (2.22g, 6.54mmol), (3, 5-dichlorophenyl) boronic acid (1.26g, 6.61mmol), bis (diphenylphosphino) ferrocene-Pd (II) & CH2Cl2Complex (0.27g, 0.33mmol) and Na2CO3The reaction mixture (1.43g, 13.5mmol) in 1, 4-dioxane (20mL) and water (10mL) was heated to 80 ℃ and stirred for 30 minutes. The reaction mixture was allowed to cool to room temperature, then diluted with water (70mL) and CH2Cl2(3X 50 mL). The combined organic layers were filtered and concentrated in vacuo. The residue was purified by column chromatography (0-30% EtOAc/cyclohexane) to give ethyl 8- (3, 5-dichlorophenyl) -4- (dimethylamino) quinoline-3-carboxylate. LCMS (method B) Rt＝1.67min，m/z＝389.0[M+H]+。
A solution of ethyl 8- (3, 5-dichlorophenyl) -4- (dimethylamino) quinoline-3-carboxylate (2.82g, 6.17mmol) in 1, 4-dioxane (20mL) was treated with water (10mL) and lithium hydroxide (0.44g, 18.5 mmol). The resulting reaction mixture was warmed to 100 ℃ and stirred overnight. The reaction mixture was allowed to cool to room temperature, then acidified to pH 2 with 2M HCl and washed with waterEtOAc (3X 30mL) extraction. Basification of the aqueous phase to pH 6 and addition of 10% MeOH/CH2Cl2(3X 30 mL). The combined organic phases were concentrated in vacuo to give 8- (3, 5-dichlorophenyl) -4- (dimethylamino) quinoline-3-carboxylic acid. LCMS (method B) Rt＝0.94min，m/z＝361.0
[M+H]+。
To a stirred suspension of 8- (3, 5-dichlorophenyl) -4- (dimethylamino) quinoline-3-carboxylic acid (160mg, 0.35mmol) in DMF (3.5mL) was added NEt3(200. mu.L, 1.42mmol) followed by 2, 3-dihydro-1, 4-benzoxazin-4-amine (67mg, 0.42mmol) and PyBOP (282mg, 0.53 mmol). The reaction was allowed to proceed at room temperature under N2Stir under atmosphere overnight. Dilute the reaction with brine and add CH2Cl2The extraction was performed twice. The crude product was purified by column chromatography eluting with cyclohexane: EtOAc (0-40% EtOAc) to afford the title compound. LCMS (method B) Rt＝1.47min，m/z＝493.0[M+H]+。1H NMR(400MHz,DMSO)[ppm]:9.04(s,1H),8.4(s,1H),8.20(dd,J＝1.6Hz,J＝8.8Hz,1H),7.69-7.71(m,1H),7.58-7.62(m,1H),7.52(d,J＝2Hz,2H),7.4(t,J＝1.6Hz,1H),6.79-6.97(m,4H),4.49(t,J＝4.4Hz,2H),3.74(t,J＝4.4Hz,2H),3.19(s,6H)。
The following compounds were prepared analogously by the method of example 5.1:
Figure BDA0003493730300000431
Figure BDA0003493730300000441
Figure BDA0003493730300000451
Figure BDA0003493730300000461
Figure BDA0003493730300000471
Figure BDA0003493730300000481
Figure BDA0003493730300000491
Figure BDA0003493730300000501
Figure BDA0003493730300000511
Figure BDA0003493730300000521
Figure BDA0003493730300000531
Figure BDA0003493730300000541
Figure BDA0003493730300000551
Figure BDA0003493730300000561
Figure BDA0003493730300000571
Figure BDA0003493730300000581
Figure BDA0003493730300000591
example 6.1
4- (3, 5-dichlorophenyl) -N- (2, 3-dihydro-1, 4-benzoxazin-4-yl) -8-morpholino-pyrido [3,2-d ] pyrimidine-7-carboxamide
Figure BDA0003493730300000592
In N2To a suspension of ethyl 6-hydroxypyrimidine-4-carboxylate (5.03g, 28.74mmol) in DMF (25mL) under atmosphere was added 1, 3-dichloro-5, 5-dimethylhydantoin (3.48g, 17.3 mmol). The mixture was stirred at room temperature overnight. The reaction was partitioned between water (200mL) and EtOAc (100mL) and then extracted with EtOAc (2X 75 mL). The combined organic layers were washed with anhydrous Na2SO4Drying, filtering and vacuum concentrating to obtain 5-chloro-6-hydroxy-pyrimidine-4-carboxylic acid ethyl ester. LCMS (method A) Rt＝0.54min，m/z＝203.0[M+H]+。
At room temperature in N2To a solution of ethyl 5-chloro-6-hydroxy-pyrimidine-4-carboxylate (8.74g, 28.1mmol) in CH under an atmosphere3To the suspension in CN (100mL) was added DIPEA (6.4mL, 36mmol) followed by phosphorus oxybromide (9.44g, 31.28 mmol). The resulting mixture was stirred at room temperature. By CH reaction2Cl2Diluted (100mL) and poured slowly into water (100 mL). Then using CH2Cl2The mixture was extracted (3X 100 mL). The combined organic layers were washed with anhydrous Na2SO4Dried, filtered and concentrated in vacuo. The oil was purified by column chromatography (0-10% EtOAc/cyclohexane) to give 6-bromo-5-chloro-pyrimidine-4-carboxylic acid ethyl ester. LCMS (method A) Rt＝0.98min，m/z＝265.0[M+H]+。
To N2Stirring under atmosphere of 6-bromo-5-chloro-pyrimidine-4-carboxylic acid ethyl ester (4.31g, 14.9mmol) and (3, 5-dichlorobenzeneTo a solution of 2.71g, 14.20mmol) of boronic acid in 1, 4-dioxane (55mL) was added K2CO3(8.69g, 62.9mmol) followed by tetrakis (triphenylphosphine) palladium (0) (732mg, 0.63mmol) was added. The reaction was degassed and placed in N2Under an atmosphere, and then heated to 90 ℃ over 16 hours. The mixture was diluted with EtOAc (50mL) and passed through
Figure BDA0003493730300000601
The combined organic filtrates were concentrated in vacuo. The residue was purified by column chromatography (0-20% EtOAc/cyclohexane) to give ethyl 5-chloro-6- (3, 5-dichlorophenyl) pyrimidine-4-carboxylate. LCMS (method B) Rt＝1.43min，m/z＝331.0[M+H]+。
At room temperature in N2To a mixture of ethyl 5-chloro-6- (3, 5-dichlorophenyl) pyrimidine-4-carboxylate (2.90g, 8.75mmol) in THF (85mL) and water (30mL) was added lithium hydroxide (624mg, 25.6mmol) under an atmosphere. The resulting mixture was heated to 50 ℃ for 1 hour. The reaction was cooled to room temperature and then concentrated under reduced pressure to remove THF. The resulting solution was diluted with water (50mL) and then acidified with 2M HCl until pH 1, allowing the solid to precipitate. The precipitate was filtered off and washed with water (25 mL). The precipitate was then dried under vacuum at 50 ℃ to give 5-chloro-6- (3, 5-dichlorophenyl) pyrimidine-4-carboxylic acid. LCMS (method B) Rt＝0.72min，m/z＝303.0[M+H]+。
A suspension of 5-chloro-6- (3, 5-dichlorophenyl) pyrimidine-4-carboxylic acid (2.49g, 7.82mmol) in thionyl chloride (30mL, 411mmol) was placed in N2Heating to 80 ℃ under atmosphere. DMF (0.5mL, 6mmol) was added and the reaction was completely dissolved. The reaction was then concentrated in vacuo, taken up in toluene (20mL) and azeotroped (3 times) to give 5-chloro-6- (3, 5-dichlorophenyl) pyrimidine-4-carbonyl chloride, which was used without further purification.
At room temperature in N2To a solution of 5-chloro-6- (3, 5-dichlorophenyl) pyrimidine-4-carbonyl chloride (2.65g, 7.82mmol) in toluene (20mL) under atmosphere was added NEt3(2mL, 14mmol) followed by the addition of ethyl 3- (dimethylamino) prop-2-enoate (1.4mL, 9.7 mmol). Reaction at room temperature under N2Stirring under an atmosphere. The reaction was diluted with EtOAc (125mL) and passed
Figure BDA0003493730300000611
And (5) filtering. Rinse with EtOAc (125mL)
Figure BDA0003493730300000612
The combined organic filtrates were concentrated in vacuo. The residue was taken up in EtOAc (250mL) and 2M HCl (aq, 100 mL). The aqueous layer was extracted with EtOAc (125 mL). The combined organic layers were washed with anhydrous Na2SO4Drying, filtering and vacuum concentrating to obtain 2- [ 5-chloro-6- (3, 5-dichlorophenyl) pyrimidine-4-carbonyl]-ethyl 3- (dimethylamino) prop-2-enoate. LCMS (method B) Rt＝1.24min，m/z＝428.0[M+H]+。
At room temperature in N2To produce 2- [ 5-chloro-6- (3, 5-dichlorophenyl) pyrimidine-4-carbonyl under atmosphere]To a solution of ethyl (3.59g, 6.29mmol) of (E) -3- (dimethylamino) prop-2-enoate in diethyl ether (25mL) and EtOH (6mL) was added 4-methoxybenzylamine (1.20mL, 9.09mmol) over 1 h. The reaction was diluted with water (150mL) and CH2Cl2(4X 75 mL). The combined organic layers were washed with brine, over anhydrous Na2SO4Drying, filtering and vacuum concentrating to obtain 2- [ 5-chloro-6- (3, 5-dichlorophenyl) pyrimidine-4-carbonyl]-3- [ (4-methoxyphenyl) methylamino]2-propenoic acid ethyl ester. The material was taken without any further purification. LCMS (method B) Rt＝1.49min，m/z＝520.0[M+H]+。
At room temperature in N2To produce 2- [ 5-chloro-6- (3, 5-dichlorophenyl) pyrimidine-4-carbonyl under atmosphere]-3- [ (4-methoxyphenyl) methylamino]To a solution of ethyl prop-2-enoate (4.4g, 5.66mmol) in DMF (15mL) was added K2CO3(2.37g, 17.1 mmol). The resulting mixture was heated to 90 ℃ for 24 hours. The reaction was cooled to room temperature, then poured into water (300mL) and quenched with CH2Cl2(3X 100 mL). The combined organic layers were washed with brine (200mL) and anhydrous Na2SO4Dried, filtered and concentrated in vacuo. The residue was purified by column chromatography (0-5% MeOH/CH)2Cl2) Purifying to obtain 4- (3, 5-dichlorophenyl) -5- [ (4-methoxyphenyl) methyl]-8-oxo-pyrido [3,2-d]Pyrimidine-7-carboxylic acid ethyl ester. LCMS (method B) Rt＝1.17min，m/z＝484.0[M+H]+。
At room temperature in N2To produce 4- (3, 5-dichlorophenyl) -5- [ (4-methoxyphenyl) methyl under atmosphere]-8-oxo-pyrido [3,2-d]Pyrimidine-7-carboxylic acid ethyl ester (1.89g, 3.70mmol) in CH2Cl2To a solution in (75mL) and DMF (0.5mL) was added oxalyl chloride (2mL, 23.1mmol) slowly. The reaction was heated to 60 ℃ and refluxed for 1 hour. The mixture was cooled to room temperature and then purified by addition of saturated NaHCO3Aqueous solution (200mL) to quench and use CH2Cl2(3X 100 mL). The combined organic layers were combined and then concentrated in vacuo to give 8-chloro-4- (3, 5-dichlorophenyl) pyrido [3,2-d]Pyrimidine-7-carboxylic acid ethyl ester. LCMS (method B) Rt＝1.52min，m/z＝382.0[M+H]+。
At room temperature in N2To the reaction solution under the atmosphere, 8-chloro-4- (3, 5-dichlorophenyl) pyrido [3,2-d]To a solution of pyrimidine-7-carboxylic acid ethyl ester (502mg, 0.93mmol) in THF (10mL, 123mmol) was added morpholine (0.17mL, 1.9mmol) dropwise. The reaction was stirred at room temperature for 3 hours. Then saturated NaHCO3The reaction was quenched with aqueous solution (50mL) and CH2Cl2(3X 25 mL). The combined organic layers were washed with anhydrous Na2SO4Dried, filtered and concentrated in vacuo. The residue was purified by column chromatography (10-25% EtOAc/cyclohexane) to give 4- (3, 5-dichlorophenyl) -8-morpholino-pyrido [3,2-d]Pyrimidine-7-carboxylic acid ethyl ester. LCMS (method B) Rt＝1.56min，m/z＝433.0[M+H]+。
At room temperature in N2To 4- (3, 5-dichlorophenyl) -8-morpholino-pyrido [3,2-d ] under atmosphere]To a mixture of pyrimidine-7-carboxylic acid ethyl ester (337.5mg, 0.717mmol) in 1, 4-dioxane (15mL) and water (5mL) was added lithium hydroxide (61.6mg, 2.52 mmol). The resulting mixture was heated to 80 ℃. The reaction was concentrated in vacuo, the residue taken up in water (20mL) and acidified with 2M HCl. The resulting precipitate was filtered off and washed with water (20mL) and then dried under vacuum at 45 ℃ overnight to give 4- (3, 5-dichlorophenyl) -8-morpholino-pyrido [3,2-d]Pyrimidine-7-carboxylic acid. LCMS (method B) Rt＝0.80min，m/z＝405.0[M+H]+。
To 4- (3, 5-dichlorophenyl) -8-morpholino-pyrido [3,2-d]To a suspension of pyrimidine-7-carboxylic acid (125.1mg, 0.31mmol) in THF (3mL) was added NEt3(0.18mL, 1.3mmol) followed by PyBOP (259mg, 0.49 mmol). Reaction at room temperature under N2Stirring under an atmosphere. 2, 3-dihydro-1, 4-benzoxazin-4-amine (60.5mg, 0.40mmol) in THF (1mL) was then added to the reaction. The mixture was stirred at room temperature for 22 hours. The mixture was diluted with brine (25mL) and CH2Cl2(3X 15 mL). The combined organic layers were washed with Na2SO4Dried, filtered and concentrated in vacuo. The residue was purified by column chromatography (5-40% EtOAc/cyclohexane) to afford the title compound. LCMS (method B) Rt＝1.38min，m/z＝537.0[M+H]+。1H NMR(400MHz,DMSO-d6)δ[ppm]:10.75(s,1H),9.38(s,1H),8.92(s,1H),8.31(d,J＝2Hz,2H),7.87(t,J＝2Hz,1H),7.01(dd,J＝1.2,8Hz,1H),6.85(td,J＝1.6,8.4Hz,1H),6.69-6.78(m,2H),4.38(t,J＝4.4Hz,2H),3.86(t,J＝4Hz,4H),3.63-3.73(m,6H)。
Example 7.1
8- (3, 5-dichlorophenyl) -N- (2, 3-dihydro-1, 4-benzoxazin-4-yl) -4-morpholino-1, 6-naphthyridine-3-carboxamide
Figure BDA0003493730300000631
To a stirred solution of 3, 4-dihydro-2H-1, 4-benzoxazine in EtOH (8mL) was added sodium nitrite (612mg, 8.87mmol) in water (3.2mL) dropwise at 0 ℃. After 5 minutes, HCl (0.8mL) was added dropwise and the reaction mixture was allowed to stir at 0 ℃ for 2 hours. NaOH (2.96g, 74mmol) in water (7.5mL) was added dropwise to the reaction mixture at 0 deg.C, followed by sodium dithionate (4.4g, 22.2 mmol). The resulting reaction mixture was heated to 90 ℃ for 4 hours. The reaction mixture was dissolved in EtOAc (20mL) and washed with water (10mL) and brine (10 mL). With anhydrous Na2SO4The organic layer was dried and concentrated in vacuo. The crude compound was purified by column chromatography eluting with 0-50% EtOAc/petroleum ether. LCMS (Square)Method C) Rt＝0.89min，m/z＝152.36[M+H]+。
A mixture of 3-bromopyridin-4-amine (10.0g, 57.8mmol) and diethyl 2- (ethoxymethylene) malonate (32.8mL, 173mmol) was heated to 120 ℃ for 16 hours. The reaction mixture was allowed to reach room temperature, reduced to dryness in vacuo and purified by column chromatography eluting with 0-50% EtOAC/petroleum ether to give 2- [ [ (3-bromo-4-pyridinyl) amino group]Methylene group]Malonic acid diethyl ester. LCMS (method C) Rt＝1.71min，m/z＝343.19[M+H]+。
2- [ [ (3-bromo-4-pyridyl) amino group]Methylene group]A solution of malonate (2.8g, 8.12mmol) in diphenyl ether (42mL) was heated to 250 ℃ for 30 minutes. The reaction mixture was allowed to cool to room temperature and petroleum ether (50mL) was added. The resulting solid compound was filtered, washed with petroleum ether (50mL) and dried in vacuo to give 8-bromo-4-hydroxy-1, 6-naphthyridine-3-carboxylic acid ethyl ester. LCMS (method C) Rt＝1.16min，m/z＝297.11[M+H]+。
To POCl3(43mL) 8-bromo-4-hydroxy-1, 6-naphthyridine-3-carboxylic acid ethyl ester (4.3g, 14.5mmol) was added and heated to 90 ℃ for 6 hours. The reaction mixture was allowed to cool to room temperature and concentrated under reduced pressure. The residue was diluted in EtOAc (100mL) and saturated NaHCO3Aqueous (3X 30mL) and brine (20 mL). With anhydrous Na2SO4The organic layer was dried and concentrated under reduced pressure. The crude product was purified by column chromatography eluting with 0-20% EtOAc/petroleum ether. LCMS (method C) Rt＝2.30min，m/z＝315.09[M+H]+。
To a stirred solution of ethyl 8-bromo-4-chloro-1, 6-naphthyridine-3-carboxylate (3g, 9.5mmol) in THF (60mL) was added morpholine (4.1g, 47.5mmol) and stirred at room temperature for 30 min. The reaction mixture was concentrated to dryness under reduced pressure. The crude product was purified by column chromatography eluting with 0-50% EtOAc/petroleum ether to give 8-bromo-4-morpholino-1, 6-naphthyridine-3-carboxylic acid ethyl ester. LCMS (method C) Rt＝1.65min，m/z＝366.24[M+H]+。
To a stirred mixture of ethyl 8-bromo-4-morpholino-1, 6-naphthyridine-3-carboxylate (0.8g, 2.18mmol) and (3, 5-dichlorophenyl) boronic acid (1.04g, 5.46 mm)ol) solution in 1, 4-dioxane/water (16/4mL) Cs was added2CO3(2.13g, 6.55mmol), followed by the addition of tri-tert-butylphosphonium tetrafluoroborate (0.127g, 0.43mmol) and a solution of N2The mixture was degassed for 10 minutes. Adding PdCl to the reaction mixture2(dppf) (0.16g, 0.21mmol) and heated to 90 ℃ for 16 hours. The reaction mixture was dissolved in EtOAc (30mL) and washed with water (15mL) and brine (10 mL). With anhydrous Na2SO4The organic layer was dried and concentrated to dryness. The crude product was purified by column chromatography eluting with 0-50% EtOAc/petroleum ether. LCMS (method C) Rt＝2.33min，m/z＝432.30[M+H]+。
To a stirred solution of ethyl 8- (3, 5-dichlorophenyl) -4-morpholino-1, 6-naphthyridine-3-carboxylate (0.55g, 1.27mmol) in EtOH: THF: water (1:1:1, 9mL) at room temperature was added LiOH2O (0.16g, 3.81mmol) and heated to 70 ℃ for 4 hours. The reaction mixture was allowed to cool to room temperature and then concentrated to remove the solvent. The pH was adjusted to 6-7 with 0.5M aqueous HCl under cooling (0 ℃) and extracted with EtOAc (3X 30 mL). The combined organic layers were washed with anhydrous Na2SO4Dried and concentrated to dryness. LCMS (method C) Rt＝2.15min，m/z＝403.9[M+H]+。
To a stirred solution of 8- (3, 5-dichlorophenyl) -4-morpholino-1, 6-naphthyridine-3-carboxylic acid (0.3g, 0.74mmol) and 2, 3-dihydro-1, 4-benzoxazin-4-amine (134mg, 0.89mmol) in DMF (5mL) at room temperature was added HATU (0.34g, 0.89mmol) and DIPEA (0.38g, 2.2 mmol). The resulting reaction mixture was heated to 60 ℃ for 16 hours. The reaction mixture was quenched by the addition of water (5mL) and extracted with EtOAc (3X 15 mL). The combined organic layers were washed with brine, over anhydrous Na2SO4Dried and concentrated under reduced pressure. The crude product was purified by column chromatography eluting with 0-100% EtOAc/petroleum ether to give the title compound. LCMS (method D) Rt＝2.12min，m/z＝536.24[M+H]+。1H NMR(400MHz,DMSO-d6)δ[ppm]:10.75(s,1H),9.03(s,1H),8.84(s,1H),7.77(d,J＝2Hz,2H),7.72(t,J＝2Hz,1H),7.03(m,1H),6.85(td,J＝2,7.2Hz,1H),6.72-6.78(m,2H),4.38(t,J＝4.4Hz,2H),3.92(t,J＝3.6Hz,4H),3.69(br s,2H),3.39(t,J＝4Hz,4H)。
Example 8.1
N- (2, 3-dihydro-1, 4-benzoxazin-4-yl) -2-methyl-4-morpholino-8- (2,3, 5-trifluorophenyl) quinoline-3-carboxamide
Figure BDA0003493730300000651
To a stirred solution of 8-bromo-1H-3, 1-benzoxazine-2, 4-dione (0.8g, 3.3mmol) and ethyl 3-oxobutyrate (0.86g, 6.61mmol) in DMA (5mL) was added NaOH (0.132g, 3.3 mmol). The resulting reaction mixture was stirred at 100 ℃ for 12 hours. The mixture was quenched by the addition of water (200mL) and extracted with EtOAc (3X 50 mL). The combined organic layers were washed with brine (50mL) and Na2SO4Dried and concentrated under reduced pressure. The crude compound was triturated with n-pentane (30mL) to give 8-bromo-4-hydroxy-2-methyl-quinoline-3-carboxylic acid ethyl ester. LCMS (method C) Rt＝1.54min，m/z＝310.22[M+H]+。
To a stirred solution of ethyl 8-bromo-4-hydroxy-2-methyl-quinoline-3-carboxylate (0.3g, 0.96mmol) in EtOH (5mL) was added KOH (0.814g, 14.5mmol) at room temperature and heated to 80 ℃ for 24 h. The reaction mixture was allowed to come to room temperature and concentrated. The pH of the residue was adjusted to 1-2 using 2N aqueous HCl and the precipitated solid was filtered, washed with water (10mL) and dried to give 8-bromo-4-hydroxy-2-methyl-quinoline-3-carboxylic acid. LCMS (method C) Rt＝1.46min，m/z＝280.05[M-H]-。
8-bromo-4-hydroxy-2-methyl-quinoline-3-carboxylic acid (0.2g, 0.7mmol) and POCl3(10mL) the mixture was heated to 90 ℃ for 2 hours. The reaction mixture was allowed to cool to room temperature and concentrated under reduced pressure to give 8-bromo-4-chloro-2-methyl-quinoline-3-carbonyl chloride.
To a stirred solution of 2, 3-dihydro-1, 4-benzoxazin-4-amine (0.188g, 1.25mmol) in THF (3mL) was added DIPEA (0.342g, 2.5mmol) and cooled to 0-5 ℃. To the reaction mixture was added a solution of 8-bromo-4-chloro-2-methyl-quinoline-3-carbonyl chloride (0.2g, 0.62mmol) in 2mL THF and allowed to stir at room temperature. By passingWater (100mL) was added to quench the reaction mixture and extracted with EtOAc (2X 50 mL). The combined organic layers were washed with brine (50mL) and Na2SO4Dried and concentrated under reduced pressure. The crude compound was purified by column chromatography to give 8-bromo-4-chloro-N- (2, 3-dihydro-1, 4-benzoxazin-4-yl) -2-methyl-quinoline-3-carboxamide. LCMS (method C) Rt 2.12min, M/z 432.06[ M + H [ ]]+。
To a stirred solution of 8-bromo-4-chloro-N- (2, 3-dihydro-1, 4-benzoxazin-4-yl) -2-methyl-quinoline-3-carboxamide (0.25g, 0.57mmol) and morpholine (0.5g, 5.77mmol) in THF (5mL) was added Et3N (0.116g, 1.15 mmol). The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched by the addition of water (100mL) and extracted with EtOAc (2X 50 mL). The combined organic layers were washed with brine, washed with Na2SO4Dried and concentrated under reduced pressure. The crude compound was triturated with ether (30mL) to give 8-bromo-N- (2, 3-dihydro-1, 4-benzoxazin-4-yl) -2-methyl-4-morpholino-quinoline-3-carboxamide. LCMS (method C) Rt 2.25min, M/z 483.49[ M + H ═]+。
To a stirred solution of 8-bromo-N- (2, 3-dihydro-1, 4-benzoxazin-4-yl) -2-methyl-4-morpholino-quinoline-3-carboxamide (0.3g, 0.62mmol) and (2,3, 5-trifluorophenyl) boronic acid (0.656g, 3.72mmol) in 1, 4-dioxane (12mL): water (3mL) was added Cs2CO3By N2The reaction mixture was degassed for 10 minutes with gas and then [ (t-Bu)3PH]BF4(0.036g, 0.12mmol) and PdCl2(dppf) (0.045g, 0.06mmol) and heating to 90 ℃ for 16 h. The reaction mixture was quenched by the addition of water (200mL) and extracted with EtOAc (2X 100 mL). The combined organic layers were washed with brine (50mL) and Na2SO4Dried and concentrated under reduced pressure. The crude compound was purified by column chromatography eluting with 10% EtOAc/petroleum ether to afford example 8.1. LCMS (method C) Rt 2.29min, M/z 535.22[ M + H ═]+。1H NMR(400MHz,DMSO)δ[ppm]:10.57(s,1H),8.31(d,J＝7.6Hz,2H)7.79(d,J＝6.4Hz,2H),7.69(t,J＝8.4Hz,1H),7.59-7.61(m,1H),7.20-7.21(m,1H),6.99(d,J＝6.8Hz,1H),6.85(td,J＝1.6,6.8Hz,1H),6.74-6.79(m,2H),4.39(t,J＝4Hz,2H),3.87(t,J＝4Hz,4H),3.72(br s,2H),3.32(br s,4H),2.55(s,3H)。
Example 8.2
N- (2, 3-dihydro-1, 4-benzoxazin-4-yl) -4-morpholino-2- (trifluoromethyl) -8- (2,3, 5-trifluorophenyl) quinoline-3-carboxamide
Figure BDA0003493730300000671
Step 1: to a stirred solution of 7-bromoindoline-2, 3-dione (2.5g, 11.06mmol) and ethyl 4,4, 4-trifluorobut-2-ynoate (1.83g, 11.06mmol) in DMF (15mL) was added Na2CO3(2.34g, 22.12mmol) followed by tert-butyl hydroperoxide (TBHP, 0.99g, 11.06 mmol). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched by the addition of water (20mL) and extracted with ethyl (2X 30 mL). The combined organic layers were washed with brine (3X 30mL) and Na2SO4Dried and concentrated under reduced pressure. The crude compound was purified by column chromatography eluting with 0-50% EtOAc/petroleum ether to give 8-bromo-4-hydroxy-2- (trifluoromethyl) quinoline-3-carboxylic acid ethyl ester. LCMS (method C) Rt 2.29min, m/z 364.14
[M+H]+。
Step 2: to a stirred solution of ethyl 8-bromo-4-hydroxy-2- (trifluoromethyl) quinoline-3-carboxylate (1.75g, 4.80mmol) in EtOH (10mL) was added KOH (5.39g, 96.12mmol) at room temperature and heated to 90 ℃ for 24 hours. The reaction mixture was allowed to come to room temperature and concentrated. The residue was adjusted to pH 1-2 using 2N aqueous HCl and the precipitated solid was filtered, washed with water (10mL), diethyl ether (20mL) and dried to give 8-bromo-4-hydroxy-2- (trifluoromethyl) quinoline-3-carboxylic acid. LCMS (method C) Rt 1.79min, M/z 335.99[ M + H ═]+。
And step 3: 8-bromo-4-hydroxy-2- (trifluoromethyl) quinoline-3-carboxylic acid (1g, 2.97mmol) and POCl3(10mL) the mixture was heated to 90 ℃ for 2 hours. The reaction mixture was allowed to come to room temperature and concentrated under reduced pressure to give 8-bromo-4-chloro-2- (trifluoromethyl) quinoline-3-carbonyl chloride.
And 4, step 4: to the stirred 2, 3-dihydro-1, 4-benzoA solution of oxazin-4-amine (0.8g, 5.36mmol) in THF (5mL) was added DIPEA and cooled to 0-5 deg.C. To the reaction mixture was added a solution of 8-bromo-4-chloro-2- (trifluoromethyl) quinoline-3-carbonyl chloride (1g, 2.68mmol) in 4mL THF and allowed to stir at room temperature for 16 hours. The reaction was quenched by the addition of water (20mL) and extracted with EtOAc (2X 30 mL). The combined organic layers were washed with brine (20mL) and Na2SO4Dried and concentrated under reduced pressure. The crude compound was purified by column chromatography eluting with 0-100% EtOAc/petroleum ether to give 8-bromo-4-chloro-N- (2, 3-dihydro-1, 4-benzoxazin-4-yl) -2- (trifluoromethyl) quinoline-3-carboxamide. LCMS (method C) Rt 2.23min, M/z 486.04[ M + H ═]+。
And 5: to a stirred solution of 8-bromo-4-chloro-N- (2, 3-dihydro-1, 4-benzoxazin-4-yl) -2- (trifluoromethyl) quinoline-3-carboxamide (0.844g, 1.73mmol) in THF (6mL) was added morpholine (1.5mL, 17.34mmol) at room temperature and stirred for 16 h. The reaction mixture was concentrated to dryness. The crude was purified by column chromatography eluting with 0-50% EtOAc/petroleum ether to give 8-bromo-N- (2, 3-dihydro-1, 4-benzoxazin-4-yl) -4-morpholino-2- (trifluoromethyl) quinoline-3-carboxamide. LCMS (method C) Rt 2.18min, M/z 537.08[ M + H ═]+。
Step 6: to a stirred solution of 8-bromo-N- (2, 3-dihydro-1, 4-benzoxazin-4-yl) -4-morpholino-2- (trifluoromethyl) quinoline-3-carboxamide and (2,3, 5-trifluorophenyl) boronic acid (0.687g, 3.91mmol) in 1, 4-dioxane (15mL): water (5mL) was added Cs2CO3(0.636g, 1.95 nmol). With N2The reaction mixture was degassed for 10 minutes with gas and then [ (t-Bu)3PH]BF4(0.075g, 0.26mmol) and PdCl2(dppf) (0.095, 0.13 mmol). The reaction mixture was heated to 90 ℃ for 16 hours. The reaction mixture was quenched by the addition of water (150mL) and extracted with EtOAc (3X 50 mL). The combined organic layers were washed with brine (30mL) and Na2SO4Dried and concentrated under reduced pressure. The crude compound was purified by column chromatography eluting with 0-14% EtOAc/petroleum ether to give example 8.2 as a white solid. LCMS (method C) Rt 2.27min, M/z 589.39[ M + H [ ]]+。1H NMR(400MHz,DMSO)δ[ppm]:10.62(s,1H),8.45(d,J＝8.4Hz,2H),8.03(d,J＝7.2Hz,2H),7.94(t,J＝8.4Hz,1H),7.65-7.67(m,1H),7.29-7.31(m,1H),7.03(d,J＝7.6Hz,1H),6.83-6.87(mz,1H),6.76-6.80(m,2H),4.39(t,J＝3.6Hz,2H),3.87(br s,4H),3.64(br s,2H),3.43(br s,4H)。
Experimental details of the compounds are in the table:
Figure BDA0003493730300000681
Figure BDA0003493730300000691
Figure BDA0003493730300000701
Figure BDA0003493730300000711
Figure BDA0003493730300000721
Figure BDA0003493730300000731
Figure BDA0003493730300000741
Figure BDA0003493730300000751
Figure BDA0003493730300000761
Figure BDA0003493730300000771
Figure BDA0003493730300000781
Figure BDA0003493730300000791
Figure BDA0003493730300000801
Figure BDA0003493730300000811
Figure BDA0003493730300000821
Figure BDA0003493730300000831
Figure BDA0003493730300000841
Figure BDA0003493730300000851
Figure BDA0003493730300000861
the compounds of formula (I) of the present invention are useful for the treatment and/or control of inter alia helminths, wherein endoparasitic nematodes and trematodes may be responsible for serious diseases in mammals and poultry. Typical nematodes for this indication are: filariaceae (filiidae), filamentous (setaridae), Haemonchus (Haemonchus), Trichostrongylus (trichostrongylis), Ostertagia (Ostertagia), Nematodirus (nematoiridus), Cooperia (Cooperia), Ascaris (Ascaris), abortus (bunostonuum), oesophagostomus (oesophagus), sabotella (Charbertia), Trichuris (Trichuris), strongylis (strongylis), trichinella (Trichonema), dictyostelus (dictyoides), dictyostelus (diclocaius), telangiecta (capillaris (cathariria), heterodera (hetkieselaria), Ascaris (Toxocara), gallinaceae (Ascaris) and Ascaris (ancyloides). Flukes include in particular the Fasciola family (Fascilideae), especially Fasciola hepatica (Fasciola hepatica).
Certain parasites of the species nematodiasis, cooperia and nodorula are parasitic on the intestinal tract of the host animal, while other parasites of the species haemonchus and ostertagia are parasitic in the stomach, and those of the species dictyocaulus are parasitic in lung tissue. Parasites of these families can be found in internal cellular tissues and organs, such as the heart, blood vessels, lymphatic vessels, and subcutaneous tissues. One particularly notable parasite is heartworm of the dog: dirofilaria immitis.
Parasites which may be treated and/or controlled by the compounds of formula (I) also include those from the class cestoidea (tapeworm), for example the family mesozoite (mesocessoidae), especially the genus mesozoite (mesocessoides), especially the midges (m.lineatus); the family of the diploideae (Dipyllidiaceae), in particular the Dipyllidium caninum (Dipyllidium caninum), the genus Youkesella (Joyeuxiella spp.), in particular the genus Joyeuxiella pasquali and Diphylleiella spp (Diplyylium spp.), and the family of the Taenidae (Taenidae), in particular the family of the Stratidia pisiformis (Taenidia pisformis), the family of the Swatidae (Taenidia Cervi), the family of the sheep tapeworms (Taeniovis), the family of the Zosteraceae (Taenidia hidaegensis), in particular the family of the Taenidia pis (Taeniella pisiformis), the family of the giant neck tapeworms (Taeniae taeniaefolia), the family of the continuous tapeworms (Taenia serias) and the genus Echinococcus (Echinococcus), most particularly the family of the sheep tapeworms, the continuous head worms, the Echinococcus; echinococcus granulosus (Echinococcus grandis) and Echinococcus multilocularis (Echinococcus multilocularis).
Furthermore, the compounds of formula (I) are suitable for the treatment and/or control of human pathogenic parasites. Among these, typical representatives appearing in the digestive tract are those of the genera ancylostomus (Ancylostoma), ostertagia (Necator), Ascaris (Ascaris), Strongyloides (Strongyloides), Trichinella (trichonella), capillarium (Capillaria), Trichuris (Trichuris), and pinworm (Enterobius). The compounds of the invention are also able to combat parasites of the genera Wuchereria (Wuchereria), Brugia (Brugia), Onchocerca (Onchocerca) and roaches (Loa) from the Trichinella (dracunulus) family, as well as Strongyloides (Strongyloides) and trichoderma (trichonella), which infect inter alia the gastrointestinal tract.
One particular parasite to be treated and/or controlled by the compounds of the present invention is heartworm (dirofilaria immitis). Particular subjects for such treatment are dogs and cats.
The compounds of the present invention may be administered alone or in the form of a composition. In practice, the compounds of the invention are generally administered in the form of a composition, i.e. mixed with at least one acceptable excipient. The proportion and nature of any acceptable excipient will be determined by the nature of the compound of the invention chosen, the chosen route of administration and, for example, standard practice in the veterinary and pharmaceutical arts.
In one embodiment, the present invention provides a composition comprising: a compound of the invention and at least one acceptable excipient.
In effecting such treatment and/or control, the compounds of the present invention may be administered in any form and route that makes the compounds bioavailable. The compounds of the present invention may be administered by a variety of routes, including orally, particularly by tablets and capsules. The compounds of the invention may be administered parenterally, more particularly by inhalation, subcutaneously, intramuscularly, intravenously, intraarterially, transdermally, intranasally, rectally, vaginally, ocularly, topically, sublingually and buccally, intraperitoneally, intraadiposally, intrathecally and via local delivery, for example by catheter or stent. One skilled in the art can readily select the appropriate form and route of administration depending on the particular characteristics of the compound selected, the disorder or condition to be treated, the stage of the disorder or condition, and other relevant circumstances. The pharmaceutical compositions of the present invention may be administered to a subject, for example, in the form of tablets, capsules, cachets, papers, lozenges, wafers (wafers), elixirs, ointments, transdermal patches, aerosols, inhalants, suppositories, drenches, solutions and suspensions.
The term "acceptable excipients" refers to those commonly used in the preparation of veterinary and pharmaceutical compositions and should be pure and non-toxic in the amounts used. They are generally solid, semi-solid, or liquid materials that, together, can serve as a vehicle or medium for the active ingredient. Some examples of acceptable Excipients are found in Remington's Pharmaceutical Sciences and Handbook of Pharmaceutical Excipients and include diluents, vehicles, carriers, ointment bases, binders, disintegrants, lubricants, glidants, sweeteners, flavoring agents, gel bases, sustained release matrices, stabilizers, preservatives, solvents, suspending agents, buffers, emulsifiers, dyes, propellants, coating agents and the like.
In one embodiment, the composition is suitable for oral administration, such as a tablet or capsule or a liquid formulation, for example a solution or suspension suitable for oral administration. In one embodiment, the composition is suitable for oral administration, such as a chewable formulation suitable for oral administration. In yet another embodiment, the composition is a liquid or semi-solid formulation suitable for parenteral administration, such as a solution or suspension or paste.
Particular compositions for use in a subject for treating and/or controlling nematodes/helminths include: a solution agent; emulsions, including classical emulsions, microemulsions and self-emulsifying compositions, which are anhydrous organic, preferably oily, compositions that form emulsions with body fluids upon application to a subject's body; suspensions (drenches for veterinary use); pour-on formulations (pour-on formulations); a food additive; powder preparation; tablets, including effervescent tablets; bolus medicine; a capsule, comprising microcapsules; and chewable treats. In particular, the composition is in the form of a tablet, capsule, food additive or chewable snack.
The compositions of the invention are prepared in a manner well known in the veterinary and pharmaceutical arts and comprise at least one compound of the invention as an active ingredient. The amount of a compound of the present invention may vary depending on the particular form thereof, and may conveniently be between 1% and about 50% by weight of the unit dosage form. The pharmaceutical compositions of the present invention are preferably formulated in unit dosage forms, each dosage typically containing from about 0.5mg to about 100mg of a compound of the present invention. One or more unit dosage forms may be employed to affect the therapeutic dosage.
In one embodiment, the present invention also provides a method of treating a parasite comprising: administering to a subject in need thereof an effective amount of a compound of formula (I) or a salt thereof, optionally further comprising an effective amount of at least one additional active compound.
In one embodiment, the present invention also provides a method of controlling parasites, comprising: administering to a subject in need thereof an effective amount of a compound of formula (I) or a salt thereof, optionally further comprising an effective amount of at least one additional active compound.
In one embodiment, the invention also provides a method of treating or controlling a parasite comprising: contacting the environment of a subject with an effective amount of a compound of formula (I) or a salt thereof, said method optionally further comprising an effective amount of at least one additional active compound.
Accordingly, the present invention provides the use of a compound of the invention as a medicament, including for the manufacture of a medicament. In one embodiment, the present invention provides the manufacture of a medicament comprising a compound of formula (I) or a salt thereof for use in the treatment of parasites. In one embodiment, the present invention provides the manufacture of a medicament comprising a compound of the present invention, or a salt thereof, for controlling parasites.
The term "treating" includes, but is not limited to, inhibiting, slowing, stopping, alleviating, ameliorating, reversing the progression or severity of an existing symptom, or preventing a disorder, condition, or disease. For example, adult heartworm infections will be treated by administration of a compound of the invention. The treatment can be applied or administered therapeutically.
The term "controlling" is meant to include, but is not limited to, reducing, alleviating or ameliorating the risk of a symptom, disorder, condition, or disease, as well as protecting an animal from a symptom, disorder, condition, or disease. Control may refer to therapeutic, prophylactic or preventative administration. It is well known that larval or immature heartworm infections may be asymptomatic, whereas infections with mature parasites are symptomatic and/or debilitating. Thus, for example, heartworm infection will be controlled by acting on the larvae or immature parasites, thereby preventing the infection from progressing to that of mature parasites.
Thus, the use of the compounds of the invention in the treatment and/or control of parasites, in particular helminths (among which endoparasitic nematodes and trematodes) means that the compounds of the invention are used to act on various forms of parasites throughout their life cycle, irrespective of whether the subject exhibits symptoms (including morbidity or mortality) and irrespective of the stage of parasite attack.
As used herein, "administering to a subject" includes, but is not limited to, cutaneous, subcutaneous, intramuscular, mucosal, submucosal, transdermal, oral, or intranasal administration. Administration may include injection or topical administration.
The terms "subject" and "patient" are meant to include human and non-human mammals, such as dogs, cats, mice, rats, guinea pigs, rabbits, ferrets, cattle, horses, sheep, goats, and pigs. It is understood that a more specific subject is a human. Furthermore, more specific subjects are mammalian pets or companion animals such as dogs and cats and furthermore mice, guinea pigs, ferrets and rabbits.
The term "effective amount" refers to an amount that gives a desired benefit to a subject and includes administration for both treatment and control. This amount will vary between individual subjects and will depend upon a variety of factors including the overall physical condition of the subject and the severity of the underlying cause of the condition to be treated, the concomitant therapy, and the amount of the compound of the invention used at a level beneficial for maintaining the desired response.
As one skilled in the art, an effective amount can be readily determined by the attending diagnostician, using known techniques and by observing results obtained under analogous circumstances. In determining the effective amount, dose, the attending diagnostician will consider a number of factors, including but not limited to: the species of the patient; its physical constitution, age and general health; the particular condition, disorder, infection, or disease involved; the extent or extent of involvement or severity of a condition, disorder or disease; the response of the individual patient; the particular compound administered; the mode of administration; the bioavailability characteristics of the administered formulation; a selected dosing regimen; concomitant medication; and other related circumstances. An effective amount of the present invention, i.e., a therapeutic dose, is expected to range from 0.5mg to 100 mg. The specific amount can be determined by the skilled person. Although these doses are based on subjects weighing from about 1kg to about 20kg, the diagnostician will be able to determine an appropriate dose for subjects whose weight falls outside of this weight range. An effective amount of the invention, i.e., a therapeutic dose, is expected to be in the range of 0.1mg/kg to 10mg/kg of subject. Dosing regimens are contemplated for daily, weekly, or monthly administration.
The compounds of the invention may be used in combination with one or more other active compounds or therapies for the treatment of one or more disorders, diseases or conditions, including parasitic treatments in need thereof. The compounds of the invention may be administered simultaneously, sequentially or separately with one or more compounds or therapies for the treatment of parasites and other disorders.
For example, when used to treat parasites including heartworm, the compounds of the invention may be combined with a macrocyclic lactone such as ivermectin, moxidectin or milbemycin oxime, or with imidacloprid (imidacloprid). Particular combinations for treating parasites include a compound of the invention and ivermectin. Another specific combination for the treatment of parasites comprises a compound of the invention and milbemycin oxime.
Thus, it is to be understood that the compositions and methods of the present invention optionally include inclusion of an effective amount of at least one additional active compound.
The activity of a compound as a parasiticide can be determined by a variety of methods, including in vitro methods and in vivo methods.
Example A
Microfilaria of filaria canina
Dirofilaria immitis microfilaria is isolated by filtration from the blood of infected donors and incubated in a suitable medium. Test compounds were diluted in DMSO and added to 96-well plates containing parasites. Plates were incubated for the required time and motility was assessed using an LCD camera imaging system. The effect of serum was tested by adding up to 20% fetal bovine serum in the assay. Percent motility inhibition values were generated relative to the mean of DMSO only wells.
For example, in this test, the following compounds from the preparation examples show EC50<0.1. mu.g/mL: 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 3.1, 3.2, 3.3, 3.4, 4.1, 5.1, 5.2, 5.3, 5.4, 5.6, 5.7, 5.8, 5.10, 5.11, 5.12, 5.13, 5.14, 5.15, 5.16, 5.17, 5.18, 5.19, 5.20, 5.21, 5.22, 5.23, 5.24, 6.1 and 7.1.
Example B1
Ruminant gastrointestinal tract (haemonchus contortus (h. contortus) larva development assay (Hc LDA)):
eggs of Haemonchus contortus were isolated from lamb faeces and allowed to hatch overnight. Test compounds were diluted in DMSO and added to 96-well plates containing appropriate media. To each well was added haemonchus contortus larvae and the plates were incubated for the required time. Motility was assessed using an LCD camera imaging system. Percent motility inhibition values were generated relative to the mean of DMSO only wells.
For example, in this test, the following compounds from the preparation examples show EC50<1. mu.g/mL: 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.8, 3.1, 3.2, 3.3, 3.4, 4.1, 5.1, 5.2, 5.3, 5.4, 5.6, 5.7, 5.8, 5.11, 5.12, 5.13, 5.14, 5.15, 5.16, 5.17, 5.18, 5.19, 5.20, 5.21, 5.22, 5.23, 5.24, 6.1 and 7.1.
Example B2
In vitro testing of other nematodes
Caenorhabditis elegans (Ce): caenorhabditis elegans developmental assay (Ce DA) measures the effect of compounds on developing nematodes. Eggs of caenorhabditis elegans were placed in 384-well plates along with food (e.coli) and treatments formulated in DMSO. Plates were incubated at 25 ℃ for 48 hours to allow nematodes to develop to the L4-stage. The effect of a compound is measured as a decrease in motility. Efficacy is expressed as% reduction in motility compared to negative control.
For example, in this test, the following compounds from the preparation examples show EC90<1μg/mL：5.23、5.35、5.36、5.41、5.45、5.47、5.48、5.49、5.54、5.55、5.56、5.57、5.58、5.59、5.60、5.61、5.62、5.63。
Example C
Gastrointestinal nematodes
Gerbils (meriones unguiculatus) were artificially infected with third instar larvae of each of t.colubriformis (Tc) and h.contortus (Hc) by gavage. The treatment is then performed orally with the test compound formulated in e.g. DMSO/PEG 2/1 at a dose ranging between 1X 3mg/kg and 1X 32mg/kg on day 6 post-infection. Three days after treatment, gerbils were euthanized and dissected to recover haemonchus contortus from the stomach and trichostrongylus colubriformis from the small intestine. Efficacy was expressed as% reduction in the number of worms compared to the placebo treated group using the Abbot formula.
The compounds of examples 3.3, 5.2, 5.3, 5.4, 5.19, 5.23 and 5.47 are > 80% effective on Hc and Tc. The effectiveness of the compounds of examples 3.1, 2.3 and 5.6 on Hc is > 80%.
Example D
Filamentous nematode
The Av model: gerbils injected subcutaneously with larvae of infective acanthochem carinatus (a. viteae, Av) are then treated by oral tube feeding with test preparations formulated in e.g. DMSO/PEG 2/1 at a dose ranging between 1 x 3mg/kg and 5 x 32mg/kg (one dose per day for 5 consecutive days). At necropsy 12 weeks post-infection, efficacy was expressed as% reduction in helminth numbers compared to placebo treated group using Abbot's formula.
The compounds of examples 2.6, 3.4, 5.4, 5.6, 5.7, 5.8, 5.19 and 5.20 were > 80% effective on Av.
Example E
Model L.s
Mice (BALB/c) were experimentally infected with stage 3 larvae of the cotton rat filarial (l.sigmodontis, L.s.) by subcutaneous injection or by exposure to infected mites. Treatment was carried out by oral tube feeding or subcutaneous injection with the test preparations formulated in DMSO/PEG at a ratio of 2/1, in a dose ranging between 1 x 3mg/kg (single dose) to 5 x 32mg/kg (one dose per day for 5 consecutive days). Worms in the peritoneum and pleural cavity were counted at necropsy 35 to 37 days post infection. Efficacy was expressed as% reduction in the number of worms compared to the placebo treated group using the Abbot formula. The effectiveness of the compounds of examples 3.3, 5.3, 5.41, 5.47, 5.48 and 5.56 on l.s. is > 80%.

Claims (27)

1. A compound of formula (I) or a salt thereof:
Figure DEST_PATH_IMAGE001
wherein:
n is 0 or 1;
X1selected from N and CR1；
X2Selected from N and CR2；
X3Selected from N and CR3；
X4Selected from N and CR4；
X5Selected from N and CR5；
X6Selected from N and CR6；
G is selected from
Figure DEST_PATH_IMAGE002
；
Figure DEST_PATH_IMAGE003
(ii) a And
Figure DEST_PATH_IMAGE004
；
m is selected from N-R13O and S;
Y1selected from the group consisting of CR8R9O, S and NR10；
Y2Selected from the group consisting of CR8R9O, S and NR10；
Wherein the radical Y1Or Y2At least one of which is CR8R9；
Z1Selected from N, O, S and CR11；
Z2Selected from the group consisting of none, N and CR11；
Z3Selected from the group consisting of none, N and CR11；
Z4Selected from N, O, S and CR11；
Wherein Z1、Z2、Z3And Z4Is not more than 2 of N and wherein Z is1And Z4Only one of them is O or S, only when Z is1Z when O or S is2Is absent, and only if Z4Z when O or S is3Is absent;
R1selected from: hydrogen; halogen; a hydroxyl group; -SH; -SC1-C4An alkyl group; (C) S (O)1-C4Alkyl groups); -S (O)2(C1-C4Alkyl groups); a cyano group; c1-C4An alkyl group; c1-C4A haloalkyl group; c1-C4-an alkoxy group; -B (OR)15)(OR16) Wherein R is15Selected from hydrogen, C at each application1-C4Alkyl and C3-C6Cycloalkyl radical, R16Selected from hydrogen, C at each application1-C4Alkyl and C3-C6Cycloalkyl, or R15And R16Together with the oxygen atom to which they are attached form a 5-to 7-membered ring, optionally substituted by 1 to 4C1-C4Alkyl substituted; -NH2；-NH(C1-C4Alkyl groups); and-N (C)1-C4Alkyl radical)2；
R2Selected from: hydrogen; halogen; a hydroxyl group; -SH; -SC1-C4An alkyl group; (C) S (O)1-C4Alkyl groups); -S (O)2(C1-C4Alkyl groups); a cyano group; c1-C4An alkyl group; c1-C4A haloalkyl group; c1-C4-an alkoxy group; -B (OR)15)(OR16) Wherein R is15Selected from hydrogen, C at each application1-C4Alkyl and C3-C6Cycloalkyl radical, R16Selected from hydrogen, C at each application1-C4Alkyl and C3-C6Cycloalkyl, or R15And R16Together with the oxygen atom to which they are attached form a 5-to 7-membered ring, optionally substituted by 1 to 4C1-C4Alkyl substituted; -NH2；-NH(C1-C4Alkyl groups); and-N (C)1-C4Alkyl radical)2；
R3Selected from: hydrogen; halogen; a hydroxyl group; -SH; -SC1-C4An alkyl group; (C) S (O)1-C4Alkyl groups); -S (O)2(C1-C4Alkyl groups); a cyano group; c1-C4An alkyl group; c1-C4A haloalkyl group; c1-C4-an alkoxy group; -B (OR)15)(OR16) Wherein R is15Selected from hydrogen, C at each application1-C4Alkyl and C3-C6Cycloalkyl radical, R16Selected from hydrogen, C at each application1-C4Alkyl and C3-C6Cycloalkyl, or R15And R16Together with the oxygen atom to which they are attached form a 5-to 7-membered ring, optionally substituted by 1 to 4C1-C4Alkyl substituted; -NH2；-NH(C1-C4Alkyl groups); and-N (C)1-C4Alkyl radical)2；
R4Selected from: halogen; a cyano group; -CHO; hydroxy radical；C1-C4An alkyl group; c2-C4An alkenyl group; c2-C4An alkynyl group; c3-C6A cycloalkyl group; c1-C4A haloalkyl group; c1-C4-alkoxy-substituted-C1-C4An alkyl group; benzyl optionally substituted with 1 to 5 halogen atoms; c1-C4An alkoxy group; -NH2；-NH(C1-C4Alkyl groups); -N (C)1-C4Alkyl radical)2；-NH(C3-C6Cycloalkyl groups); -N (C)1-C4Alkyl) (C3-C6-cycloalkyl); -N (C)1-C4Alkyl) (4-to 7-membered heterocycloalkyl); -NH (4-to 7-membered heterocycloalkyl); -N (C)1-C4Alkyl) (C1-C4Alkoxy groups); -C (O) NH (C)1-C4Alkyl groups); -C (O) N (C)1-C4Alkyl radical)2；-C(O)N(C1-C4Alkyl) (4-to 7-membered heterocycloalkyl); -NHSO2(C1-C4Alkyl groups); -SC1-C4An alkyl group; (O) C1-C4An alkyl group; -SO2C1-C4An alkyl group; -B (OR)15)(OR16) Wherein R is15Selected from hydrogen, C at each application1-C4Alkyl and C3-C6Cycloalkyl radical, R16Selected from hydrogen, C at each application1-C4Alkyl and C3-C6Cycloalkyl, or R15And R16Together with the oxygen atom to which they are attached form a 5-to 7-membered ring, optionally substituted by 1 to 4C1-C4Alkyl substituted; 6-or 10-membered aryl; a monocyclic heterocycle selected from the group consisting of 4-to 7-membered heterocycloalkyl, a 5-membered heteroaryl having at least one nitrogen atom through which the 5-membered heteroaryl ring is connected to the remainder of the molecule, and a 6-membered heteroaryl having at least one nitrogen atom; r4Wherein each of the aryl, heterocycloalkyl and heteroaryl rings is optionally substituted with 1,2 or 3 substituents independently selected from halogen, cyano, nitro, hydroxy, oxo, C1-C4Alkyl radical, C3-C6Cycloalkyl radical, C1-C4Haloalkyl group、C1-C4Alkoxy, -NH2、-NH(C1-C4Alkyl), -N (C)1-C4Alkyl radical)2、-NH(C3-C6Cycloalkyl), -N (C)1-C4Alkyl) (C3-C6-cycloalkyl), -NHSO2(C1-C4Alkyl), -SC1-C4Alkyl, -S (O) C1-C4Alkyl, -SO2C1-C4Alkyl, -S (O) C1-C4-haloalkyl and-SO2C1-C4Substituted with a substituent of haloalkyl; wherein R is4C in (1)3-C6The cycloalkyl and heterocycloalkyl rings are optionally substituted with a spirocyclic group, wherein said spirocyclic group is a 3-to 6-membered cycloalkyl or a 4-to 6-membered heterocycloalkyl containing 1,2 or 3 heteroatoms independently selected from N, S or O, wherein said spirocyclic group is optionally substituted with 1,2 or 3 heteroatoms independently selected from halogen, cyano, nitro, hydroxy, oxo, C1-C4Alkyl radical, C3-C6Cycloalkyl radical, C1-C4Haloalkyl, C1-C4Alkoxy, -NH2、-NH(C1-C4Alkyl), -N (C)1-C4Alkyl radical)2、-NH(C3-C6Cycloalkyl), -N (C)1-C4Alkyl) (C3-C6-cycloalkyl), -NHSO2(C1-C4Alkyl), -SC1-C4Alkyl, -S (O) C1-C4Alkyl, -SO2C1-C4Alkyl, -S (O) C1-C4-haloalkyl and-SO2C1-C4Substituted with a substituent of haloalkyl; and wherein R4Each of C1-C4Alkyl radical, C3-C6Cycloalkyl and C1-C4Alkoxy can be optionally selected from 1,2 or 3 independently selected from halogen, hydroxyl, NH2、-NH(C1-C4Alkyl), -N (C)1-C4Alkyl radical)2Cyano, carboxy, carbamoyl, C1-C4Alkoxycarbonyl, -C (O) NH (C)1-C4Alkyl), -C (O) N (C)1-C4Alkyl radical)2And C1-C4Substituted by a substituent of alkoxy;
R5selected from: hydrogen; halogen; a hydroxyl group; -SH; -SC1-C4An alkyl group; (C) S (O)1-C4Alkyl groups); -S (O)2(C1-C4Alkyl groups); a cyano group; c1-C4An alkyl group; c1-C4A haloalkyl group; c1-C4-an alkoxy group; -B (OR)15)(OR16) Wherein R is15Selected from hydrogen, C at each application1-C4Alkyl and C3-C6Cycloalkyl radical, R16Selected from hydrogen, C at each application1-C4Alkyl and C3-C6Cycloalkyl, or R15And R16Together with the oxygen atom to which they are attached form a 5-to 7-membered ring, optionally substituted by 1 to 4C1-C4Alkyl substituted; -NH2；-NH(C1-C4Alkyl groups); and-N (C)1-C4Alkyl radical)2；
R6Selected from: hydrogen; halogen; a hydroxyl group; -SH; -SC1-C4An alkyl group; (C) S (O)1-C4Alkyl groups); -S (O)2(C1-C4Alkyl groups); a cyano group; c1-C4An alkyl group; c1-C4A haloalkyl group; c1-C4-an alkoxy group; -B (OR)15)(OR16) Wherein R is15Selected from hydrogen, C at each application1-C4Alkyl and C3-C6Cycloalkyl radical, R16Selected from hydrogen, C at each application1-C4Alkyl and C3-C6Cycloalkyl, or R15And R16Together with the oxygen atom to which they are attached form a 5-to 7-membered ring, optionally substituted by 1 to 4C1-C4Alkyl substituted; -NH2；-NH(C1-C4Alkyl groups); and-N (C)1-C4Alkyl radical)2；
R7Selected from: hydrogen; c1-C4An alkyl group; and C optionally substituted by 1 to 5 halogen atoms3-C6A cycloalkyl group; -C (H) O; c2-C4An alkenyl group; c2-C4An alkynyl group; c1-C4A haloalkyl group; and C1-C4-an alkoxy group;
R8independently at each selection from hydrogen, fluorine and C1-C4An alkyl group;
R9independently at each selection from hydrogen, fluorine and C1-C4An alkyl group;
R10selected from hydrogen and C1-C4An alkyl group;
R11independently at each selection from hydrogen, halogen, hydroxy, cyano, C1-C4Alkyl radical, C1-C4Haloalkyl, C1-C4-alkoxy, C3-C6Cycloalkyl, -NH2、-NH(C1-C4Alkyl) and-N (C)1-C4Alkyl radical)2；
Q is selected from:
(i) 6-or 10-membered aryl, optionally substituted with 1,2,3, 4 or 5 independently selected from halogen, cyano, nitro, hydroxy, C1-C4Alkyl radical, C1-C4Haloalkyl, C1-C4Alkoxy radical, C3-C6Cycloalkyl, -NH2、-NH(C1-C4Alkyl), -N (C)1-C4Alkyl radical)2、-NH(C3-C6Cycloalkyl), -N (C)1-C4Alkyl) (C3-C6-cycloalkyl), -NHSO2(C1-C4Alkyl), -SC1-C4Alkyl, -S (O) C1-C4Alkyl, -SO2C1-C4Alkyl, -S (O) C1-C4-haloalkyl and-SO2C1-C4Haloalkyl, wherein said 6-or 10-membered aryl is optionally fused to a 4-to 7-membered heterocycloalkyl having 1 or 2 heteroatoms selected from O, S and N, and wherein the carbon of said heterocycloalkyl is optionally substituted with 1,2 or 3Independently selected from halogen, cyano, nitro, hydroxy, oxo, C1-C4Alkyl radical, C3-C6Cycloalkyl radical, C1-C4Haloalkyl, C1-C4Alkoxy, -NH2、-NH(C1-C4Alkyl) and-N (C)1-C4Alkyl radical)2And any N in the heterocycloalkyl is selected from hydrogen, C, where the valence allows1-C4Alkyl and C3-C6Cycloalkyl, substituted with a substituent;
(ii) a 5-to 10-membered heteroaryl having 1,2, or 3 heteroatoms independently selected from O, S and N, and wherein the carbon of the 5-to 10-membered heteroaryl is optionally substituted with 1,2,3, 4, or 5 heteroatoms independently selected from halogen, cyano, nitro, hydroxy, C1-C4Alkyl radical, C3-C6Cycloalkyl radical, C1-C4Haloalkyl, C1-C4Alkoxy, benzyloxy, -NH2、-NH(C1-C4Alkyl), -N (C)1-C4Alkyl radical)2、-SC1-C4Alkyl, -S (O) C1-C4Alkyl, -SO2C1-C4Alkyl, -S (O) C1-C4-haloalkyl and-SO2C1-C4Haloalkyl, and any N in the heteroaryl is optionally substituted, as permitted by the valence, with a substituent selected from hydrogen, C1-C4Alkyl and C3-C6Cycloalkyl, substituted with a substituent;
(iii) 4-to 7-membered heterocycloalkyl having 1,2 or 3 heteroatoms independently selected from O, S and N, wherein said heterocycloalkyl is optionally benzo-fused, wherein the carbons of said 4-to 7-membered heterocycloalkyl or optionally benzo-fused 4-to 7-membered heterocycloalkyl are optionally substituted with 1,2,3 or 4 heteroatoms independently selected from halogen, cyano, nitro, hydroxy, oxo, C1-C4Alkyl radical, C3-C6Cycloalkyl radical, C1-C4Haloalkyl, C1-C4Alkoxy, -NH2、-NH(C1-C4Alkyl) and-N (C)1-C4Alkyl radical)2And any N in the heterocycloalkyl is optionally selected from hydrogen, C1-C4Alkyl and C3-C6Cycloalkyl, substituted with a substituent;
(iv) 6-or 10-membered aryloxy, optionally substituted with 1,2 or 3 independently selected from halogen, cyano, nitro, hydroxy, C1-C4Alkyl radical, C3-C6Cycloalkyl radical, C1-C4Haloalkyl, C1-C4Alkoxy, -NH2、-NH(C1-C4Alkyl group), N (C)1-C4Alkyl radical)2、-NH(C3-C6Cycloalkyl), -N (C)1-C4Alkyl) (C3-C6-cycloalkyl), -NHSO2(C1-C4Alkyl), -SC1-C4Alkyl, -S (O) C1-C4Alkyl, -SO2C1-C4Alkyl, -S (O) C1-C4-haloalkyl and-SO2C1-C4Substituted with a substituent of haloalkyl;
(v) 6-or 10-membered arylthioxy, optionally substituted by 1,2 or 3 substituents independently selected from halogen, cyano, nitro, hydroxy, C1-C4Alkyl radical, C3-C6Cycloalkyl radical, C1-C4Haloalkyl, C1-C4Alkoxy, -NH2、-NH(C1-C4Alkyl group), N (C)1-C4Alkyl radical)2、-NH(C3-C6Cycloalkyl), -N (C)1-C4Alkyl) (C3-C6-cycloalkyl), -NHSO2(C1-C4Alkyl), -SC1-C4Alkyl, -S (O) C1-C4Alkyl, -SO2C1-C4Alkyl, -S (O) C1-C4-haloalkyl and-SO2C1-C4Substituted with a substituent of haloalkyl; and
(vi) 5-to 10-membered heteroaryloxy, optionally substituted with 1,2 or 3 substituents independently selected from halogen, cyano, nitro, hydroxy, oxo, C1-C4Alkyl radical, C3-C6Cycloalkyl radical, C1-C4Haloalkyl, C1-C4Alkoxy, -NH2、-NH(C1-C4Alkyl group), N (C)1-C4Alkyl radical)2、-NH(C3-C6Cycloalkyl), -N (C)1-C4Alkyl) (C3-C6-cycloalkyl), -NHSO2(C1-C4Alkyl), -SC1-C4Alkyl, -S (O) C1-C4Alkyl, -SO2C1-C4Alkyl, -S (O) C1-C4-haloalkyl and-SO2C1-C4Substituted with a substituent of haloalkyl;
R13selected from hydroxy, C1-C4Alkoxy and-NH2(ii) a And
R14independently selected at each selection from hydrogen, halogen, cyano, nitro, hydroxy, C1-C4Alkyl radical, C3-C6Cycloalkyl radical, C1-C4Haloalkyl, C1-C4Alkoxy radical, C1-C4Haloalkoxy, -NH2、-NH(C1-C4Alkyl) and-N (C)1-C4Alkyl radical)2。
2. A compound or salt thereof according to claim 1, wherein X1Is CR1；X2Is CR2；X3Is CR3；X4Is CR4；X5Is CR5(ii) a And X6Is N.
3. A compound or salt thereof according to claim 1, wherein X1Is CR1；X2Is CR2；X3Is CR3；X4Is CR4；X5Is N; and X6Is N.
4. A compound or salt thereof according to claim 1, wherein X1Is CR1；X2Is CR2；X3Is CR3；X4Is CR4；X5Is N; and X6Is CR6。
5. A compound or salt thereof according to any one of claims 1 to 4, wherein
Q is 6-or 10-membered aryl optionally substituted with 1,2 or 3 substituents independently selected from halogen, cyano, nitro, hydroxy, C1-C4Alkyl radical, C1-C4Haloalkyl, C1-C4Alkoxy radical, C3-C6Cycloalkyl, -NH2、-NH(C1-C4Alkyl group), N (C)1-C4Alkyl radical)2、-NH(C3-C6Cycloalkyl), -N (C)1-C4Alkyl) (C3-C6-cycloalkyl), -NHSO2(C1-C4Alkyl), -SC1-C4Alkyl, -S (O) C1-C4Alkyl, -SO2C1-C4Alkyl, -S (O) C1-C4-haloalkyl and-SO2C1-C4Substituted by a substituent of a haloalkyl group.
6. A compound or salt thereof according to any one of claims 1 to 4, wherein
Q is 6-membered aryl optionally substituted with 1,2 or 3 substituents independently selected from halogen, cyano, nitro, hydroxy, C1-C4Alkyl radical, C1-C4Haloalkyl, C1-C4Alkoxy radical, C3-C6Cycloalkyl, -NH2、-NH(C1-C4Alkyl), -N (C)1-C4Alkyl radical)2、-NH(C3-C6Cycloalkyl), -N (C)1-C4Alkyl) (C3-C6-cycloalkyl), -NHSO2(C1-C4Alkyl), -SC1-C4Alkyl, -S (O) C1-C4Alkyl, -SO2C1-C4Alkyl, -S (O) C1-C4-haloalkyl and-SO2C1-C4Haloalkyl, wherein the 6-membered aryl is fused to a 4-to 7-membered heterocycloalkyl having 1 or 2 heteroatoms selected from O, S and N, and wherein the carbon of the heterocycloalkyl is optionally substituted with 1,2 or 3 substituents independently selected from halogen, cyano, nitro, hydroxy, oxo, C1-C4Alkyl radical, C3-C6Cycloalkyl radical, C1-C4Haloalkyl, C1-C4Alkoxy, -NH2、-NH(C1-C4Alkyl) and-N (C)1-C4Alkyl radical)2And any N in the heterocycloalkyl group is selected from hydrogen, C1-C4Alkyl and C3-C6Cycloalkyl substituents.
7. A compound or salt thereof according to any one of claims 1 to 4, wherein
Q is a 5-to 10-membered heteroaryl having 1 or 2 heteroatoms selected from O, S and N, and wherein the carbon of the heteroaryl is optionally substituted with 1,2 or 3 heteroatoms independently selected from halogen, cyano, nitro, -OH, C1-C4Alkyl radical, C3-C6Cycloalkyl radical, C1-C4Haloalkyl, C1-C4Alkoxy, -NH2、-NH(C1-C4Alkyl) and-N (C)1-C4Alkyl radical)2And any N in said heteroaryl is optionally substituted by a substituent selected from hydrogen, C1-C4Alkyl and C3-C6Cycloalkyl substituents.
8. A compound or salt thereof according to any one of claims 1 to 4, wherein
Q is a 4-to 7-membered heterocycloalkyl having 1 or 2 heteroatoms selected from O, S and N, wherein the heterocycloalkyl is optionally benzofused, wherein the carbon of the heterocycloalkyl or optionally benzofused heterocycloalkyl is optionally substituted with 1,2,3 or 4 heteroatoms independently selected from halogen, cyano, nitro, hydroxy, oxo, cyano, nitro, hydroxy,C1-C4Alkyl radical, C3-C6Cycloalkyl radical, C1-C4Haloalkyl, C1-C4Alkoxy, -NH2、-NH(C1-C4Alkyl) and-N (C)1-C4Alkyl radical)2And any N in the heterocycloalkyl is optionally selected from hydrogen, C1-C4Alkyl and C3-C6Cycloalkyl substituents.
9. A compound or salt thereof according to any one of claims 1 to 8 wherein n is 1.
10. A compound or salt thereof according to any one of claims 1 to 9, wherein Y1Is CR8R9And Y is2Is O.
11. A compound or salt thereof according to any one of claims 1 to 10, wherein R4Is selected from C1-C4Alkyl radical, C3-C6Cycloalkyl, -N (C)1-C4Alkyl radical)2And 4-to 7-membered heterocycloalkyl.
12. A compound or salt thereof according to any one of claims 1 to 11, wherein
G is
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(ii) a And
m is O.
13. A compound or salt thereof according to any one of claims 1 to 11, wherein
G is
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(ii) a And
m is O.
14. A compound of formula (I) or a salt thereof according to claim 1 having formula (Ia-5),
Figure DEST_PATH_IMAGE007
；
wherein R is1、R4And Q is as defined in claim 1.
15. The compound of formula (Ia-5) or a salt thereof according to claim 14, wherein R1Is hydrogen, halogen or cyano.
16. A compound of formula (Ia-5) or a salt thereof according to claim 14 or claim 15, wherein R1Is hydrogen or fluorine.
17. A compound of formula (Ia-5) or a salt thereof according to any one of claims 14-16, wherein R4Is 4-morpholino or dimethylamino.
18. A compound of formula (Ia-5) or a salt thereof according to any one of claims 14-17, wherein Q is 6-membered aryl, optionally substituted with 1,2,3, 4 or 5 independently selected from halogen, cyano, nitro, hydroxy, C1-C4Alkyl radical, C1-C4Haloalkyl, C1-C4Alkoxy radical, C3-C6Cycloalkyl, -NH2、-NH(C1-C4Alkyl), -N (C)1-C4Alkyl radical)2、-NH(C3-C6Cycloalkyl), -N (C)1-C4Alkyl) (C3-C6-cycloalkyl), -NHSO2(C1-C4Alkyl), -SC1-C4Alkyl, -S (O) C1-C4Alkyl, -SO2C1-C4Alkyl, -S (O) C1-C4-haloalkyl and-SO2C1-C4Substituted by a substituent of haloalkyl, whereinSaid 6-or 10-membered aryl is optionally fused with a 4-to 7-membered heterocycloalkyl having 1 or 2 heteroatoms selected from O, S and N, and wherein the carbon of said heterocycloalkyl is optionally substituted with 1,2 or 3 heteroatoms independently selected from halogen, cyano, nitro, hydroxy, oxo, C1-C4Alkyl radical, C3-C6Cycloalkyl radical, C1-C4Haloalkyl, C1-C4Alkoxy, -NH2、-NH(C1-C4Alkyl) and-N (C)1-C4Alkyl radical)2And any N in the heterocycloalkyl is selected from hydrogen, C, where the valence allows1-C4Alkyl and C3-C6Cycloalkyl substituents.
19. A compound of formula (Ia-5) or a salt thereof according to any one of claims 14-18, wherein Q is selected from:
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；
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；
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；
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；
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；
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；
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；
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；
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；
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；
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；
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；
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；
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；
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；
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；
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；
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；
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；
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；
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(ii) a And
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。
20. the compound of claim 1, selected from the group consisting of:
n- [8- (3, 5-dichlorophenyl) -4- (dimethylamino) -3-quinolinyl ] -2, 3-dihydro-1, 4-benzoxazine-4-carboxamide; example 1.1
8- (3, 5-dichlorophenyl) -N- (2, 3-dihydro-1, 4-benzoxazin-4-yl) -4- (dimethylamino) -1, 7-naphthyridine-3-carboxamide; (example 2.1)
8- (3, 5-dichlorophenyl) -N- (3, 4-dihydro-2H-quinolin-1-yl) -4- (dimethylamino) -1, 7-naphthyridine-3-carboxamide; (example 2.2)
8- (3, 5-dichlorophenyl) -N- (2, 3-dihydro-1, 4-benzoxazin-4-yl) -4-morpholino-1, 7-naphthyridine-3-carboxamide; (example 2.3)
8- (3, 5-dichlorophenyl) -N- (2, 3-dihydro-1, 4-benzoxazin-4-yl) -4- (dimethylamino) -1, 5-naphthyridine-3-carboxamide; (example 3.1)
5- (3, 5-dichlorophenyl) -N- (2, 3-dihydro-1, 4-benzoxazin-4-yl) -1- (dimethylamino) naphthalene-2-carboxamide; (example 4.1) and
8- (3, 5-dichlorophenyl) -N- (2, 3-dihydro-4H-benzo [ b ] [1,4] oxazin-4-yl) -4- (dimethylamino) quinoline-3-carboxamide; (example 5.1)
Or a salt of any of the foregoing.
21. The compound of claim 1, selected from the group consisting of:
n- (2, 3-dihydro-1, 4-benzoxazin-4-yl) -4-morpholino-8- (2,3, 5-trifluorophenyl) -1, 7-naphthyridine-3-carboxamide; (example 2.4)
N- (2, 3-dihydro-1, 4-benzoxazin-4-yl) -4- [ methoxy (methyl) amino ] -8- (2,3, 5-trifluorophenyl) -1, 7-naphthyridine-3-carboxamide; (example 2.5)
8- [ 3-chloro-5- (trifluoromethyl) phenyl ] -N- (2, 3-dihydro-1, 4-benzoxazin-4-yl) -4-morpholino-1, 7-naphthyridine-3-carboxamide; (example 2.6)
N- (2, 3-dihydro-1, 4-benzoxazin-4-yl) -4-morpholino-8- (2, 3-dichlorophenyl) -1, 7-naphthyridine-3-carboxamide; (example 2.7)
8- (3, 5-dichloro-4-fluoro-phenyl) -N- (2, 3-dihydro-1, 4-benzoxazin-4-yl) -4-morpholino-1, 7-naphthyridine-3-carboxamide; (example 2.8)
8- (5-chloro-3-pyridinyl) -N- (2, 3-dihydro-1, 4-benzoxazin-4-yl) -4-morpholino-1, 7-naphthyridine-3-carboxamide; (example 2.9)
N- (2, 3-dihydro-1, 4-benzoxazin-4-yl) -4-thiomorpholino-8- (2,3, 5-trifluorophenyl) -1, 7-naphthyridine-3-carboxamide; (example 2.10)
N- (2, 3-dihydro-1, 4-benzoxazin-4-yl) -4- (1, 1-dioxo-1, 4-thiazinan-4-yl) -8- (2,3, 5-trifluorophenyl) -1, 7-naphthyridine-3-carboxamide; (example 2.11)
N- (2, 3-dihydro-1, 4-benzoxazin-4-yl) -4-morpholino-8- (3,4, 5-trifluorophenyl) -1, 7-naphthyridine-3-carboxamide; (example 2.12)
8- (2, 3-dichlorophenyl) -N- (2, 3-dihydro-1, 4-benzoxazin-4-yl) -4- (dimethylamino) -1, 5-naphthyridine-3-carboxamide; (example 3.2)
8- (3, 5-dichlorophenyl) -N- (2, 3-dihydro-1, 4-benzoxazin-4-yl) -4-morpholino-1, 5-naphthyridine-3-carboxamide; (example 3.3)
N- (2, 3-dihydro-1, 4-benzoxazin-4-yl) -4-morpholino-8- (2,3, 5-trifluorophenyl) -1, 5-naphthyridine-3-carboxamide; (example 3.4)
8- (2, 3-dichlorophenyl) -N- (2, 3-dihydro-1, 4-benzoxazin-4-yl) -4-morpholino-quinoline-3-carboxamide; (example 5.2)
8- (3, 5-dichlorophenyl) -N- (2, 3-dihydro-1, 4-benzoxazin-4-yl) -4-morpholino-quinoline-3-carboxamide; (example 5.3)
N- (2, 3-dihydro-1, 4-benzoxazin-4-yl) -7-fluoro-4-morpholino-8- (2,3, 5-trifluorophenyl) quinoline-3-carboxamide; (example 5.4)
8- (5-chloro-3-pyridinyl) -N- (2, 3-dihydro-1, 4-benzoxazin-4-yl) -4-morpholino-quinoline-3-carboxamide; (example 5.5)
N- (2, 3-dihydro-1, 4-benzoxazin-4-yl) -4-morpholino-8- (2,3, 5-trifluorophenyl) quinoline-3-carboxamide; (example 5.6)
8- (3, 5-dichlorophenyl) -N- (2, 3-dihydro-1, 4-benzoxazin-4-yl) -7-fluoro-4-morpholino-quinoline-3-carboxamide; (example 5.7)
8- (3, 5-difluorophenyl) -N- (2, 3-dihydro-1, 4-benzoxazin-4-yl) -7-fluoro-4-morpholino-quinoline-3-carboxamide; (example 5.8)
N- (2, 3-dihydro-1, 4-benzoxazin-4-yl) -4-morpholino-8-pyrimidin-5-yl-quinoline-3-carboxamide; (example 5.9)
N- (2, 3-dihydro-1, 4-benzoxazin-4-yl) -4-thiomorpholino-8- (2,3, 5-trifluorophenyl) quinoline-3-carboxamide; (example 5.10)
8- [ 2-chloro-6- (trifluoromethyl) -4-pyridinyl ] -N- (2, 3-dihydro-1, 4-benzoxazin-4-yl) -4-morpholino-quinoline-3-carboxamide; (example 5.11)
8- (2, 6-dichloro-4-pyridinyl) -N- (2, 3-dihydro-1, 4-benzoxazin-4-yl) -4-morpholino-quinoline-3-carboxamide; (example 5.12)
8- (3, 5-dichloro-2-fluoro-phenyl) -N- (2, 3-dihydro-1, 4-benzoxazin-4-yl) -4-morpholino-quinoline-3-carboxamide; (example 5.13)
8- (5-chloro-2-fluoro-3-pyridinyl) -N- (2, 3-dihydro-1, 4-benzoxazin-4-yl) -4-morpholino-quinoline-3-carboxamide; (example 5.14)
N- (2, 3-dihydro-1, 4-benzoxazin-4-yl) -4- (1, 1-dioxo-1, 4-thiazinan-4-yl) -8- (2,3, 5-trifluorophenyl) quinoline-3-carboxamide; (example 5.15)
N- (2, 3-dihydro-1, 4-benzoxazin-4-yl) -4-morpholino-8- (2,4, 5-trifluorophenyl) quinoline-3-carboxamide; (example 5.16)
8- (6-chloropyrazin-2-yl) -N- (2, 3-dihydro-1, 4-benzoxazin-4-yl) -4-morpholino-quinoline-3-carboxamide; (example 5.17)
8- (4, 5-dichloro-3-pyridinyl) -N- (2, 3-dihydro-1, 4-benzoxazin-4-yl) -4-morpholino-quinoline-3-carboxamide; (example 5.18)
8- (5-chloro-2, 3-difluoro-phenyl) -N- (2, 3-dihydro-1, 4-benzoxazin-4-yl) -4-morpholino-quinoline-3-carboxamide; (example 5.19)
N- (2, 3-dihydro-1, 4-benzoxazin-4-yl) -4-morpholino-8- (2,3,4, 5-tetrafluorophenyl) quinoline-3-carboxamide; (example 5.20)
8- (4-chloro-5-fluoro-3-pyridinyl) -N- (2, 3-dihydro-1, 4-benzoxazin-4-yl) -4-morpholino-quinoline-3-carboxamide; (example 5.21)
8- [ 4-chloro-6- (trifluoromethyl) -2-pyridinyl ] -N- (2, 3-dihydro-1, 4-benzoxazin-4-yl) -4-morpholino-quinoline-3-carboxamide; (example 5.22)
8- (3, 5-dichloro-2, 4-difluoro-phenyl) -N- (2, 3-dihydro-1, 4-benzoxazin-4-yl) -4-morpholino-quinoline-3-carboxamide; (example 5.23)
N-indolin-1-yl-4-morpholino-8- (2,3, 5-trifluorophenyl) quinoline-3-carboxamide; (example 5.24)
8- (4, 6-dichloro-2-pyridinyl) -N- (2, 3-dihydro-1, 4-benzoxazin-4-yl) -4-morpholino-quinoline-3-carboxamide; (example 5.25)
N- (2, 3-dihydro-1, 4-benzoxazin-4-yl) -8- (6-fluoropyrazin-2-yl) -4-morpholino-quinoline-3-carboxamide; (example 5.26)
8- [ 2-chloro-6- (trifluoromethyl) pyrimidin-4-yl ] -N- (2, 3-dihydro-1, 4-benzoxazin-4-yl) -4-morpholino-quinoline-3-carboxamide; (example 5.27)
8- (6-chloro-5-fluoro-2-pyridinyl) -N- (2, 3-dihydro-1, 4-benzoxazin-4-yl) -4-morpholino-quinoline-3-carboxamide; (example 5.28)
8- (6-chloro-3-fluoro-2-pyridinyl) -N- (2, 3-dihydro-1, 4-benzoxazin-4-yl) -4-morpholino-quinoline-3-carboxamide; (example 5.29)
N- (2, 3-dihydro-1, 4-benzoxazin-4-yl) -8- (6-ethoxypyrazin-2-yl) -4-morpholino-quinoline-3-carboxamide; (example 5.30)
4- (azetidin-1-yl) -N- (2, 3-dihydro-1, 4-benzoxazin-4-yl) -8- (2,3, 5-trifluorophenyl) quinoline-3-carboxamide; (example 5.31)
N- (2, 3-dihydro-1, 4-benzoxazin-4-yl) -4-pyrrolidin-1-yl-8- (2,3, 5-trifluorophenyl) quinoline-3-carboxamide; (example 5.32)
N- (2, 3-dihydro-1, 4-benzoxazin-4-yl) -4- [ 2-methoxyethyl (methyl) amino ] -8- (2,3, 5-trifluorophenyl) quinoline-3-carboxamide; (example 5.33)
4- [ bis (2-methoxyethyl) amino ] -N- (2, 3-dihydro-1, 4-benzoxazin-4-yl) -8- (2,3, 5-trifluorophenyl) quinoline-3-carboxamide; (example 5.34)
7-cyano-8- (3, 5-dichlorophenyl) -N- (2, 3-dihydro-1, 4-benzoxazin-4-yl) -4-morpholino-quinoline-3-carboxamide; (example 5.35)
4-cyclopropyl-N- (2, 3-dihydro-1, 4-benzoxazin-4-yl) -8- (2,3, 5-trifluorophenyl) quinoline-3-carboxamide; (example 5.36)
N- (2, 3-dihydro-1, 4-benzoxazin-4-yl) -4- (3-fluoroazetidin-1-yl) -8- (2,3, 5-trifluorophenyl) quinoline-3-carboxamide; (example 5.37)
N- (2, 3-dihydro-1, 4-benzoxazin-4-yl) -4- (3-hydroxyazetidin-1-yl) -8- (2,3, 5-trifluorophenyl) quinoline-3-carboxamide; (example 5.38)
N- (2, 3-dihydro-1, 4-benzoxazin-4-yl) -4-oxazolidin-3-yl-8- (2,3, 5-trifluorophenyl) quinoline-3-carboxamide; (example 5.39)
N- (2, 3-dihydro-1, 4-benzoxazin-4-yl) -4- (2-oxa-6-azaspiro [3.3] heptan-6-yl) -8- (2,3, 5-trifluorophenyl) quinoline-3-carboxamide; (example 5.40)
N- (2, 3-dihydro-1, 4-benzoxazin-4-yl) -7-fluoro-4-morpholino-8- (3,4, 5-trifluorophenyl) quinoline-3-carboxamide; (example 5.41)
4- (3, 5-dichlorophenyl) -N- (2, 3-dihydro-1, 4-benzoxazin-4-yl) -8-morpholino-pyrido [3,2-d ] pyrimidine-7-carboxamide; (example 6.1) and
8- (3, 5-dichlorophenyl) -N- (2, 3-dihydro-1, 4-benzoxazin-4-yl) -4-morpholino-1, 6-naphthyridine-3-carboxamide; (example 7.1)
Or a salt of any of the foregoing.
22. The compound of claim 1, selected from the group consisting of:
n- (2, 3-dihydro-1, 4-benzoxazin-4-yl) -4-isoxazolidin-2-yl-8- (2,3, 5-trifluorophenyl) quinoline-3-carboxamide; (example 5.42)
N- (2, 3-dihydro-1, 4-benzoxazin-4-yl) -4-morpholino-8- [1- (2,2, 2-trifluoroethyl) pyrazol-4-yl ] quinoline-3-carboxamide; (example 5.43)
8- (2, 6-dichloropyrimidin-4-yl) -N- (2, 3-dihydro-1, 4-benzoxazin-4-yl) -4-morpholino-quinoline-3-carboxamide; (example 5.44)
N- (2, 3-dihydro-1, 4-benzoxazin-4-yl) -4-tetrahydropyran-4-yl-8- (2,3, 5-trifluorophenyl) quinoline-3-carboxamide; (example 5.45)
4- [ acetyl (methyl) amino ] -N- (2, 3-dihydro-1, 4-benzoxazin-4-yl) -8- (2,3, 5-trifluorophenyl) quinoline-3-carboxamide; (example 5.46)
8- (3, 5-dichloro-2-fluoro-phenyl) -N- (2, 3-dihydro-1, 4-benzoxazin-4-yl) -7-fluoro-4-morpholino-quinoline-3-carboxamide; (example 5.47)
8- (3, 5-dichloro-2, 4-difluoro-phenyl) -N- (2, 3-dihydro-1, 4-benzoxazin-4-yl) -7-fluoro-4-morpholino-quinoline-3-carboxamide; (example 5.48)
N- (2, 3-dihydro-1, 4-benzoxazin-4-yl) -4-morpholino-8- (2,3, 6-trifluoro-4-pyridinyl) quinoline-3-carboxamide; (example 5.49)
N- (2, 3-dihydro-1, 4-benzoxazin-4-yl) -8- (4-fluoro-2, 6-dimethyl-phenyl) -4-morpholino-quinoline-3-carboxamide; (example 5.50)
N- (2, 3-dihydro-1, 4-benzoxazin-4-yl) -8- [ 4-ethylsulfanyl-6- (trifluoromethyl) pyrimidin-2-yl ] -4-morpholino-quinoline-3-carboxamide; (example 5.51)
8- [ 4-benzyloxy-6- (trifluoromethyl) pyrimidin-2-yl ] -N- (2, 3-dihydro-1, 4-benzoxazin-4-yl) -4-morpholino-quinoline-3-carboxamide; (example 5.52)
[3- (2, 3-dihydro-1, 4-benzoxazin-4-ylcarbamoyl) -8- (2,3, 5-trifluorophenyl) -4-quinolinyl ] boronic acid; (example 5.53)
8- (3, 5-dichloro-2, 4-difluoro-phenyl) -7-fluoro-N-indolin-1-yl-4-morpholino-quinoline-3-carboxamide; (example 5.54)
N- (2, 3-dihydro-1, 4-benzoxazin-4-yl) -4- (1-methoxyethyl) -8- (2,3, 5-trifluorophenyl) quinoline-3-carboxamide; (example 5.55)
8- (3, 5-dichloro-2, 4-difluoro-phenyl) -N- (2, 3-dihydro-1, 4-benzoxazin-4-yl) -4- (dimethylamino) -7-fluoro-quinoline-3-carboxamide; (example 5.56)
N- (2, 3-dihydro-1, 4-benzoxazin-4-yl) -4-morpholino-8- (2,3,5, 6-tetrafluorophenyl) quinoline-3-carboxamide; (example 5.57)
4-cyclopropyl-8- (3, 5-dichloro-2, 4-difluoro-phenyl) -N- (2, 3-dihydro-1, 4-benzoxazin-4-yl) -7-fluoro-quinoline-3-carboxamide; (example 5.58)
8- [3, 5-bis (trifluoromethyl) phenyl ] -N- (2, 3-dihydro-1, 4-benzoxazin-4-yl) -7-fluoro-4-morpholino-quinoline-3-carboxamide; (example 5.59)
8- (5-chloro-2, 3-difluoro-phenyl) -N- (2, 3-dihydro-1, 4-benzoxazin-4-yl) -7-fluoro-4-morpholino-quinoline-3-carboxamide; (example 5.60)
8- [ 3-chloro-5- (trifluoromethyl) phenyl ] -N- (2, 3-dihydro-1, 4-benzoxazin-4-yl) -7-fluoro-4-morpholino-quinoline-3-carboxamide; (example 5.61)
8- (3, 5-dichloro-2, 4-difluoro-phenyl) -N- (2, 3-dihydro-1, 4-benzoxazin-4-yl) -7-fluoro-4- [ methoxy (methyl) amino ] quinoline-3-carboxamide; (example 5.62)
N- (2, 3-dihydro-1, 4-benzoxazin-4-yl) -4-morpholino-8- [4- (trifluoromethyl) phenyl ] quinoline-3-carboxamide; (example 5.63)
8- [3, 5-dichloro-4- (trifluoromethyl) phenyl ] -N- (2, 3-dihydro-1, 4-benzoxazin-4-yl) -4-morpholino-quinoline-3-carboxamide; (example 5.64)
8- (3-chloro-2, 5, 6-trifluoro-phenyl) -N- (2, 3-dihydro-1, 4-benzoxazin-4-yl) -7-fluoro-4-morpholino-quinoline-3-carboxamide; (example 5.65)
8- (3-chloro-5-cyano-phenyl) -N- (2, 3-dihydro-1, 4-benzoxazin-4-yl) -4-morpholino-quinoline-3-carboxamide; (example 5.66)
8- (3-cyano-2, 5-difluoro-phenyl) -N- (2, 3-dihydro-1, 4-benzoxazin-4-yl) -4-morpholino-quinoline-3-carboxamide; (example 5.67)
N- (2, 3-dihydro-1, 4-benzoxazin-4-yl) -4- (2,2, 2-trifluoro-1-methyl-ethyl) -8- (2,3, 5-trifluorophenyl) quinoline-3-carboxamide; (example 5.68)
N- (2, 3-dihydro-1, 4-benzoxazin-4-yl) -2-methyl-4-morpholino-8- (2,3, 5-trifluorophenyl) quinoline-3-carboxamide; (example 8.1) and
n- (2, 3-dihydro-1, 4-benzoxazin-4-yl) -4-morpholino-2- (trifluoromethyl) -8- (2,3, 5-trifluorophenyl) quinoline-3-carboxamide; (example 8.2)
Or a salt of any of the foregoing.
23. A composition comprising a compound or salt thereof according to any one of claims 1-22 and at least one acceptable carrier.
24. Use of a compound according to any one of claims 1 to 22, or a salt thereof, as a medicament.
25. Use of a compound according to any one of claims 1 to 22, or a salt thereof, in the manufacture of a medicament for the treatment of endoparasites.
26. Use of a compound or salt thereof according to any one of claims 1 to 22 in the manufacture of a medicament for the treatment of heartworm.
27. Use of a compound or salt thereof according to any one of claims 1 to 22 in the manufacture of a medicament for the control of heartworm.
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